Interpreting variants of uncertain significance (VUS) in mismatch repair (MMR) genes remains a major challenge in managing Lynch syndrome and other hereditary cancer syndromes. This review outlines recommended VUS classi...Interpreting variants of uncertain significance (VUS) in mismatch repair (MMR) genes remains a major challenge in managing Lynch syndrome and other hereditary cancer syndromes. This review outlines recommended VUS classification procedures, encompassing foundational and specialized methodologies tailored for MMR genes by expert organizations, including InSiGHT and ClinGen's Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (VCEP). Key approaches include: (1) functional data, encompassing direct assays measuring MMR proficiency such as in vitro MMR assays, deep mutational scanning, and MMR cell-based assays, as well as techniques like methylation-tolerant assays, proteomic-based approaches, and RNA sequencing, all of which provide critical functional evidence supporting variant pathogenicity; (2) computational data/tools, including in silico meta-predictors and models, which contribute to robust VUS classification when integrated with experimental evidence; and (3) enhanced variant detection to identify the actual causal variant through whole-genome sequencing and long-read sequencing to detect pathogenic variants missed by traditional methods. These strategies improve diagnostic precision, support clinical decision-making for Lynch syndrome, and establish a flexible framework that can be applied to other OMIM-listed genes.
In patients with Familial Adenomatous Polyposis (FAP), large desmoid tumors can develop all over the body. However, the most frequent presentation is as large intra-abdominal masses, usually located in the mesentery of t...In patients with Familial Adenomatous Polyposis (FAP), large desmoid tumors can develop all over the body. However, the most frequent presentation is as large intra-abdominal masses, usually located in the mesentery of the small bowel. From there, they tend to grow and invade both the abdominal wall and/or the retroperitoneal structures. This can cause life-threatening complications such as recurrent abdominal sepsis with fistulation and damage to vital organs. In selected patients, the only option may be radical resection and replacement by intestinal transplantation (ITx). We aimed to review all the current literature on ITx for FAP-related desmoids and provide an update from the largest single-center experience (2007-2024). All patients undergoing ITx for FAP-related desmoid were included. Between 2007 and 2024, 166 ITx was performed in 158 patients at Addenbrooke's Hospital, Cambridge, UK. Of these, 20 (12%) were for desmoid associated with FAP (10 modified multivisceral transplants, 8 isolated ITx and 2 liver-containing grafts). The five-year all-cause patient survival was 92%, median follow-up was 4.3 years. As the patients presented with very advanced disease, many technical challenges were faced such as: extensive ureteric involvement, abdominal wall fistulation, management of previously formed ileo-anal pouches and extra-abdominal recurrences. Graft selection was another evolving issue, as foregut resection- versus sparing techniques require careful preoperative risk stratification due to increased long-term cancer risk in FAP patients. For certain patients with advanced FAP/desmoid disease, ITx can allow for a radical resection with excellent survival and functional outcomes. However, there is a high degree of initial morbidity associated with the operation and patients should be appropriately counselled. Graft selection and degree of native organ resection requires a careful balanced discussion.
Loehrer E, Wagner A, Bahar M
… +11 more, Ramzan FR, Jelsig AM, Goverde A, van Leerdam M, Korsse SE, Dekker E, Spaander MCW, Karstensen JG, Zuber V, Macrae F, Latchford A
BACKGROUND: Female patients with Peutz-Jeghers syndrome (PJS) have an increased risk of breast cancer (BrCa), and surveillance is recommended. However, clinicopathological features of their tumors and prognosis are lacki...BACKGROUND: Female patients with Peutz-Jeghers syndrome (PJS) have an increased risk of breast cancer (BrCa), and surveillance is recommended. However, clinicopathological features of their tumors and prognosis are lacking. To facilitate more precise future guideline development, we evaluated these data. METHODS: We conducted an international survey for InSiGHT members to collect retrospective data on PJS patients with diagnosed breast cancer. RESULTS: We received 23 responses, including three centers with data on BrCa patients. All reported BrCa patients were female. In total, the cohort comprised 27 patients with 34 BrCa (five bilateral synchronous, one bilateral metachronous, and one metachronous unilateral tumours). The median age at first cancer diagnosis was 45 years (range 26-67). Most cancers were ductal carcinoma, either invasive (13) or in situ (DCIS; 19). TNM staging for invasive cancer was available in thirteen cases, of which nine were T1N0M0. Among tumors with histological reports, 14/15 were oestrogen receptor positive, 8/15 were progesterone receptor positive, and 4/15 were HER2 positive. There were no triple negative breast cancers. Twenty-five patients had follow-up data, comprising 229 patient years. Eleven patients had died of any cause during follow-up. Survival at 5 years was 73%. CONCLUSION: Overall, breast cancers that occur in this PJS population seem to have favorable characteristics and prognosis. These data will help inform discussions about risk management in patients with PJS. Further research is needed to better understand lifetime risk, the optimal surveillance modality and its outcomes.
Adenomatous polyposis syndromes are hereditary conditions characterised by the development of multiple adenomas in the gastrointestinal tract, particularly in the colon and rectum, significantly increasing the risk of co...Adenomatous polyposis syndromes are hereditary conditions characterised by the development of multiple adenomas in the gastrointestinal tract, particularly in the colon and rectum, significantly increasing the risk of colorectal cancer and, in some cases, extra-colonic malignancies. These syndromes are caused by germline pathogenic variants (PVs) in genes involved in Wnt signalling and DNA repair. The main autosomal dominant adenomatous polyposis syndromes include familial adenomatous polyposis (FAP) and polymerase proofreading-associated polyposis (PPAP), caused by germline PVs in APC and the POLE and POLD1 genes, respectively. Autosomal recessive syndromes include those caused by biallelic PVs in the DNA mismatch repair genes MLH1, MSH2, MSH6, PMS2, MSH3 and probably MLH3, and in the base excision repair genes MUTYH, NTHL1 and MBD4. This review provides an in-depth discussion of the genetic and molecular mechanisms underlying hereditary adenomatous polyposis syndromes, their clinical presentations, tumour mutational signatures, and emerging approaches for the treatment of the associated cancers. Considerations for genetic testing are described, including post-zygotic mosaicism, non-coding PVs, the interpretation of variants of unknown significance and cancer risks associated with monoallelic variants in the recessive genes. Despite advances in genetic testing and the recent identification of new adenomatous polyposis genes, many cases of multiple adenomas remain genetically unexplained. Non-genetic factors, including environmental risk factors, prior oncologic treatments, and bacterial genotoxins colonising the intestine - particularly colibactin-producing Escherichia coli - have emerged as alternative pathogenic mechanisms.
In the majority of patients with a classical Familial Adenomatous Polyposis (FAP) a pathogenic APC germline variant is identified; usually these are truncating variants in the coding region of APC. However, there are som...In the majority of patients with a classical Familial Adenomatous Polyposis (FAP) a pathogenic APC germline variant is identified; usually these are truncating variants in the coding region of APC. However, there are some special circumstances in which FAP is not the result of a pathogenic heterozygous germline variant in APC (mosaicism) and tspecific APC variants which do not cause FAP (I1307K and promotor variants). This paper will discuss these three conditions. APC somatic (postzygotic) mosaicism can be identified in up to 50% of unexplained adenomatous polyposis cases. The ability to identify APC postzygotic mosaicism depends on the the detection method (today usually next-generation sequencing) and also the tissue being analysed (investigation of multiple colorectal adenomas is more sensitive than leukocyte DNA). Identifying mosaicism has important implications in terms of an individual's management and managing risk in family members. The I1307K variant in APC is prevalent among Ashkenazi Jews (AJ) but can also be found in Sephardi Jews and individuals of non-Jewish descent. While this variant does not cause polyposis, it increases the risk of colorectal cancer (CRC) by 1.68-fold in AJ individuals. However, the link between the I1307K variant and CRC risk in non-AJ populations, is less well-established. Furthermore, its potential impact on other types of cancer remains unclear. Consequently, the classification of this variant, along with appropriate screening and surveillance recommendations, remains a subject of ongoing debate among leading medical and genetic organizations. Variants in the APC promotor 1B region cause the relatively newly described condition of gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). It is said to have an isolated gastric phenotype, with neither duodenal, large bowel nor extra-intestinal manifestations. There are many uncertainties regarding this condition, it's penetrance and management. Lack of clinical data and poor understanding of the natural history of the condition remain significant barriers to developing guidelines to manage this condition.
The St Mark's Hospital Polyposis Registry was founded in 1924, the first such unit in the world. This paper documents the development of the unit over the subsequent 100 years, which was inextricably linked to scientific...The St Mark's Hospital Polyposis Registry was founded in 1924, the first such unit in the world. This paper documents the development of the unit over the subsequent 100 years, which was inextricably linked to scientific and clinical advance in the field of polyposis syndromes.
Approximately 30% of sebaceous skin lesions (or sebaceous neoplasia) demonstrate DNA mismatch repair (MMR)-deficiency. MMR-deficiency can be caused by Lynch syndrome, resulting from germline pathogenic variants in the DN...Approximately 30% of sebaceous skin lesions (or sebaceous neoplasia) demonstrate DNA mismatch repair (MMR)-deficiency. MMR-deficiency can be caused by Lynch syndrome, resulting from germline pathogenic variants in the DNA MMR genes MLH1, MSH2, MSH6 and PMS2, but other causes include somatic MLH1 gene promoter hypermethylation, constitutional MLH1 gene promoter hypermethylation (MLH1 epimutation), or biallelic somatic MMR gene mutations. In colorectal (CRCs) and endometrial cancers (ECs), tumour MMR-deficiency showing loss of MLH1 and PMS2 protein expression (MLH1/PMS2-deficiency) is predominantly caused by somatic MLH1 hypermethylation, however, it is not clear if somatic MLH1 hypermethylation is a cause of MLH1/PMS2-deficiency in sebaceous neoplasia. This study investigated the causes of MLH1/PMS2-deficiency in 28 cases with sebaceous neoplasia. Germline pathogenic variants in MLH1 were identified in 11 of 28 cases. Of the remaining 17 non-Lynch syndrome cases, two (11.8%) were positive for MLH1 hypermethylation in blood-derived DNA (constitutional MLH1 epimutations). The corresponding sebaceous tissue of these two cases also showed MLH1 hypermethylation. None of the other eight cases with sufficient sebaceous tissue-derived DNA for testing showed somatic MLH1 hypermethylation. Multi-gene panel testing of sebaceous tissue and matched blood-derived DNA identified four cases with biallelic somatic MLH1 mutations as the cause of MLH1/PMS2-deficiency. No cause of MLH1/PMS2-deficiency could be identified in one case. This study demonstrates that biallelic somatic MLH1 mutations and constitutional MLH1 epimutations underlie MLH1/PMS2-deficiency in sebaceous neoplasms after excluding Lynch syndrome. Unlike CRCs and ECs, somatic MLH1 hypermethylation was not identified suggesting it is not a common cause of MLH1/PMS2-deficiency in sebaceous neoplasia.
Recent updated management guidelines for Familial Adenomatous Polyposis (FAP) have been published by professional bodies internationally. These recommendations reflect the diverse needs and capabilities of varying health...Recent updated management guidelines for Familial Adenomatous Polyposis (FAP) have been published by professional bodies internationally. These recommendations reflect the diverse needs and capabilities of varying health systems worldwide, including thresholds for intervention and population health priorities. Whilst guidelines are closely aligned in many regards, there are areas of disparity. However, alongside discrepancies in guideline recommendations, common challenges also face professional bodies across the globe. Generation of a robust evidence-base in the environment of limited data is difficult in rare diseases such as FAP, underscored by the fact that expert consensus opinion underpins virtually all guidelines. The presence of a wide phenotypic spectrum in FAP and the other hereditary gastrointestinal polyposis syndromes, whilst now well recognised, further complicates the creation of universal recommendations. In this review we draw comparison between the various international guidelines for the management of FAP, using examples to focus on thematic areas of agreement and divergence. However, beyond this, we also wish to highlight the persisting evidence gaps in clinical management, and any areas of ongoing debate among clinicians, where we are yet to establish the optimal approach.
The European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS) established in 2017 and connecting more than 50 European expert centres improves access to diagnosis, treatment, and the provision of high-qu...The European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS) established in 2017 and connecting more than 50 European expert centres improves access to diagnosis, treatment, and the provision of high-quality healthcare for patients with rare genetic tumour risk syndromes (hereditary cancer), no matter where they live in Europe.
Women with inherited BRCA1/2 mutations are at increased risk of breast and ovarian cancer. The reports on the prevalence and spectrum of these mutations have been primarily focused on individuals with European ancestry....Women with inherited BRCA1/2 mutations are at increased risk of breast and ovarian cancer. The reports on the prevalence and spectrum of these mutations have been primarily focused on individuals with European ancestry. A previous study on Iranian breast cancer patients reported no BRCA1/2 mutation in early-onset breast cancer with no other criteria, which is contrary to other populations. The purpose of this study was to characterize the patterns of these mutations in Iranian breast and ovarian cancer patients and evaluate the predictive efficacy of the Manchester scoring system in patients and their unaffected family members. We retrospectively reviewed the genetic testing performed for breast and ovarian cancer patients and unaffected individuals with a positive family history. The study participants were selected based on the NCCN (National Comprehensive Cancer Network) criteria (version 2.2024). A total of 376 female breast cancer patients, 49 ovarian cancer patients, and 74 unaffected individuals were enrolled in this study. In breast cancer patients, 24 (6.4%) BRCA1 and 23 (6.1%) BRCA2 mutations were detected. In ovarian cancer patients, 9 (18.5%) BRCA1 and 1 (2%) BRCA2 mutations were identified. Three (4.1%) BRCA2 mutations were identified in unaffected individuals. Seven breast cancer patients with age of cancer diagnosis ≤ 40 and no other criteria (including family history) had an underlying mutation: Four BRCA2, and three BRCA1 mutations. The Manchester score performed well, with a sensitivity of 81% and a specificity of 70%. More research is needed to clarify the hereditary component of breast and ovarian cancer in Iranian patients.
It has been suggested that women with a pathogenic variant (mutation) in BRCA1 or BRCA2 are at a higher risk of developing high-grade endometrial cancer. Furthermore, significantly higher follicular (but lower luteal) en...It has been suggested that women with a pathogenic variant (mutation) in BRCA1 or BRCA2 are at a higher risk of developing high-grade endometrial cancer. Furthermore, significantly higher follicular (but lower luteal) endometrial thickness, a surrogate marker for endometroid adenocarcinoma risk, has been reported for this high-risk population. Given that medications known to affect endometrial thickness (i.e., tamoxifen, oral contraceptives) are often indicated for BRCA mutation carriers, it is important to elucidate substantial differences exist in carriers. Thus, we conducted a retrospective chart review of endometrial thickness among women with a BRCA1 or BRCA2 who had an intact uterus and were referred to a specialized ovarian cancer clinic between 2007 and 2016. Clinical data was collected from chart review, while endometrial thickness (millimeters; mm) was abstracted from transvaginal ultrasound reports with endometrial dating and compared to published levels in the general population. In total, 114 women were identified, 73 of whom were premenopausal and 41 who were postmenopausal. Among premenopausal women, the median follicular endometrial thickness found was 7.00 mm (n = 40, range 3-13) compared to 6.8 mm (range 2.4-14) in non-carriers and the median luteal endometrial thickness was 10.85 mm (n = 30, range 5-18), compared to 9.6 mm (range 3.3-18.2) in non-carriers. Among postmenopausal women, the median menopausal endometrial thickness was 4.0 mm (n = 41, range 1-18) compared to 4.0 mm (range 1-25) in non-carrier controls. Although based on small numbers, we found no significant difference in the endometrial thickness of BRCA mutation carriers versus non-carriers.
Telomere biology disorders (TBDs) are a group of genetic conditions characterized by defects in telomere maintenance leading to multisystemic organ involvement and a predisposition to hematologic malignancies. The manage...Telomere biology disorders (TBDs) are a group of genetic conditions characterized by defects in telomere maintenance leading to multisystemic organ involvement and a predisposition to hematologic malignancies. The management of patients with TBDs who develop acute myeloid leukemia (AML) presents a significant challenge due to their limited bone marrow reserve and non-hematopoietic organ dysfunction. We present the case of a 45-year-old patient with a previously unrecognized TBD who presented with AML. The patient's history of longstanding cytopenias, idiopathic avascular necrosis, and pulmonary fibrosis were suggestive of a TBD, which was confirmed through telomere length testing and the presence of a TERT variant. Due to his underlying TBD, he was treated with dose-reduced azacitidine and venetoclax, adapting the approach commonly employed in elderly, co-morbid AML patients ineligible for intensive chemotherapy. This resulted in a complete remission with incomplete count recovery that has persisted for greater than 12 months to date. Aside from prolonged myelosuppression, the patient tolerated the regimen well with minimal toxicity. To our knowledge, this is the first report of the successful utilization of azacitidine and venetoclax as an AML treatment modality in TBD patients and underscores the potential of this regimen as an effective non-intensive treatment strategy for high grade myeloid neoplasms arising in the context of inherited bone marrow failure syndromes.
Lynch syndrome is one of the most common hereditary cancer predisposition syndromes, which is caused by germline pathogenic variants in mismatch repair genes. It is associated with increased risks of colorectal cancer, e...Lynch syndrome is one of the most common hereditary cancer predisposition syndromes, which is caused by germline pathogenic variants in mismatch repair genes. It is associated with increased risks of colorectal cancer, endometrial cancer and various other types of cancer. With the rapid development in economy, medicine and genetic tests technology in recent decades, China had achieved significant advancements in the screening, diagnosis and treatment of Lynch syndrome. However, there are still a lot of challenges remaining unresolved. The major challenges include inconsistent access to genetic tests and counseling, regional disparities in healthcare quality, and limited implementation of clinical guidelines. This review will focus on the Chinese current status in the screening of Lynch syndrome, cancer surveillance, preventive measures, patients' willingness to take genetic tests and share genetic information, insurance coverage of medical cost, and national collaboration. At the end, we also summarize the major current research themes in Lynch syndrome in China.
Schei-Andersen AJ, Witjes VM, Vos JR
… +7 more, Mensenkamp AR, van Altena A, Schieving J, Simons M, Schuurs-Hoeijmakers JHM, PTEN Study Group, Hoogerbrugge N
Increased hereditary cancer risk is one of the hallmarks of PTEN Hamartoma Tumor Syndrome (PHTS) which is caused by a pathogenic germline variant in PTEN. Case reports and some cohort studies have described ovarian cance...Increased hereditary cancer risk is one of the hallmarks of PTEN Hamartoma Tumor Syndrome (PHTS) which is caused by a pathogenic germline variant in PTEN. Case reports and some cohort studies have described ovarian cancer (OC) in PHTS patients. Previously, we observed an enrichment of non-serous OC in PHTS compared to sporadic cases (3% vs 1%). However, ovarian cancer is currently not considered a PHTS-related cancer. The aim of this study was to describe five PHTS patients with a pathogenic germline variant in PTEN with non-serous OC. Three of the non-serous OCs were mucinous carcinomas (49, 51 and 52 years) and two were malignant germ cell tumors (8 and 15 years) and all were diagnosed before genetic testing and PHTS diagnosis. In addition to OC, the described patients developed other PHTS-related benign and malignant lesions. We provide further evidence that non-serous ovarian cancer, especially mucinous, endometrioid and malignant germ cell tumors should be further investigated as potential PHTS-related cancers.
There is frequent uncertainty in both the precise quantification of risk, and the application of clinical interventions, designed to mitigate increased heritable colorectal cancer (CRC) susceptibility. We evaluated the r...There is frequent uncertainty in both the precise quantification of risk, and the application of clinical interventions, designed to mitigate increased heritable colorectal cancer (CRC) susceptibility. We evaluated the role of a collaborative specialist multidisciplinary team meeting (MDM) for familial and hereditary CRC, led by the St Mark's Hospital Centre for Familial Intestinal Cancer specifically in supporting the clinical management of uncertainty. A retrospective thematic analysis of meeting outcomes from inception in June 2020 until March 2023 was performed. Descriptive statistics were employed to ascertain clinicopathological data, clinical queries and whether MDM recommendations were outside the scope of current guidelines. In total 260 cases were discussed from 13 regional institutions. A prior personal history of cancer was present in 215 (82.6%), and a family history of CRC in 107(41.2%) and non-CRC 27(10.4%) cases. In thematic analysis uncertainty related to indications for genetic testing was considered in 148 (56.9%) of cases, with unexplained mismatch repair deficiency (u-dMMR) in 78 (30%) of cases, and resolution of molecular interpretation in 61 (23.5%). Surveillance related queries represented 55 (21.1%), and mainstreaming 29 (11%) of cases. Management was recommended beyond the scope of existing guidelines in 64 (24.6%) cases. This regional hereditary CRC MDM provides clinicians with support in areas of uncertainty in diagnosis and clinical management, supporting clinical decision-making where evidence and clinical guidelines may be limited. This model could be replicated to support complexity in clinical care in other geographical regions or other health conditions.
Cascade testing is often recommended for cancer predisposition syndromes, like Lynch syndrome (LS), to identify at-risk family members. The uptake of cascade testing is typically meditated by the proband's willingness to...Cascade testing is often recommended for cancer predisposition syndromes, like Lynch syndrome (LS), to identify at-risk family members. The uptake of cascade testing is typically meditated by the proband's willingness to disclose their results with family members. Of which, cascade testing uptake rates in Singapore has been low, compared to global rates. Studies suggest that healthcare providers (HCPs)-meditated contact of at-risk family improves uptake, yet few have explored how receptive probands and family members are to such a model. Moreover, no studies to date have examined such a model of cascade testing in Asia. To address this gap, we interviewed 17 participants (probands and relatives) in Singapore to evaluate the acceptability and feasibility of HCP-mediated cascade testing for families with LS. Our findings show broad acceptability for HCP-mediated disclosure to relatives, driven by a sense of beneficence. However, HCP involvement introduced three unique issues to disclosure process: (i) their clinical position, which conveys expertise and authority; (ii) relational complexities within family dynamics; and (iii) the notion of family-centric privacy. We propose that HCP-mediated disclosure may be best implemented through a cooperative and flexible process, tailored to each family's unique circumstances. This approach balances the efficiency of providing accurate genetic information whilst sensitively navigating familial relationships, thereby improving uptake while respecting cultural and relational nuances.
Multiple endocrine neoplasia type 4 (MEN4) is caused by a germline CDKN1B deleterious variant. CDKN1B encodes p27Kip1, a cyclin-dependent kinase inhibitor that acts as tumor-suppressor. Clinical presentation of MEN4 is s...Multiple endocrine neoplasia type 4 (MEN4) is caused by a germline CDKN1B deleterious variant. CDKN1B encodes p27Kip1, a cyclin-dependent kinase inhibitor that acts as tumor-suppressor. Clinical presentation of MEN4 is similar to multiple endocrine neoplasia type 1 (MEN1) but the diagnosis of MEN4 can only be established once a germline CDKN1B pathogenic variant has been confirmed. We describe a unique case presenting with two -rare endocrine conditions. A 59-year-old female patient was diagnosed with medullary thyroid cancer (MTC) without evidence of a germline pathogenic variant in the RET proto-oncogene. Five years later, she developed Cushing's disease. A heterozygous germline variant was identified in the CDKN1B gene, specifically c.536del (p.Prol179GlnfsTer46), corresponding to a single-nucleotide deletion at position 536. This variant induces a frameshift, leading to an alternative stop codon. Immunostaining of the pituitary and thyroid tumors revealed a weak nuclear expression of p27/Kip1 without significant differences of expression between tumor and non-tumoral tissues. The NGS panel (Oncomine Comprehensive Assay v3) performed in both MTC and pituitary tissues identified the germline CDKN1B variant, as well as a pathogenic missense somatic variant c.182 A > G, p.(Gln61Arg) in HRAS in the MTC, without any RET somatic pathogenic variant. Evaluation of loss of heterozygosity (LOH) in both MTC and pituitary tissues showed compatibility with copy-neutral LOH, although further evidence is required for definitive confirmation. In conclusion, we report a clinical case of MTC coexisting with MEN4 due to a novel CDKN1B germline heterozygote frameshift variant.
PURPOSE: Management of cancer risks associated with the CHEK2 gene, a moderate penetrance breast cancer gene, is challenging in real-world practice. Family history, traditional breast cancer risk factors, and specific ge...PURPOSE: Management of cancer risks associated with the CHEK2 gene, a moderate penetrance breast cancer gene, is challenging in real-world practice. Family history, traditional breast cancer risk factors, and specific genetic CHEK2 variants are risk modifiers in this setting and add complexity for surveillance and risk-reduction decisions. Here, we present a case series of Brazilian CHEK2 carriers affected by breast cancer. METHODS: Patients evaluated in the Oncogenetics Department of Hospital Sírio-Libanês (Brasília, Brazil) between November 2017 and September 2021, who had a personal history of breast cancer and a germline genetic test with a pathogenic or likely pathogenic CHEK2 variant, were selected for case description. Clinical pearls and knowledge gaps were highlighted for each case. RESULTS: Twelve women were included in this descriptive analysis. All patients had early-stage breast cancer. Most of them were diagnosed with breast cancer prior to age 50 (9/12) and had a close relative affected by breast cancer (9/12). Seven patients harbored intronic pathogenic variants. Clinical pearls included the following: lack of risk estimates for intronic CHEK2 variants among non-European ancestry CHEK2 carriers, environmental exposures as a risk modifier, notable non-breast cancer diagnosis at young ages, incidental germline finding during tumor profiling, breast cancer diagnosis before the recommended age of breast cancer screening, family history of breast cancer as a risk modifier, and clinical outcomes after breast cancer treatment. CONCLUSIONS: Improvements in cancer risk assessment and cancer prevention for CHEK2 carriers are still needed to overcome current clinical challenges on the management of these patients.