Serrated Polyposis Syndrome (SPS) is characterized by multiple and/or large serrated polyps in the colon and an increased risk of colorectal cancer (CRC). The etiology is largely unknown, but in a subset of patients with...Serrated Polyposis Syndrome (SPS) is characterized by multiple and/or large serrated polyps in the colon and an increased risk of colorectal cancer (CRC). The etiology is largely unknown, but in a subset of patients with SPS, monoallelic pathogenic variants in RNF43 are detected. To date, however, the penetrance and phenotypic spectrum of patients carrying pathogenic variants (PV) in RNF43 are poorly described. We present eight patients both with and without serrated polyps from four unrelated families with likely pathogenic variants (LPV) in RNF43 and compare the results to current literature. The patients were referred to genetic counseling due to suspicion of hereditary cancer. They underwent genetic testing with custom NGS gene panels including RNF43 as part of a routine genetic work-up. Three LPVs, one multi-exon deletion and two nonsense variants, were detected in four families. Family I had a history of CRC and serrated polyps, but in the three other families (II‒IV) there was no history of CRC or serrated polyps. Colonoscopies in the probands of these families did not reveal any serrated polyps and/or CRC despite some of them being relatively old. Our findings suggest that the penetrance of RNF43-related disease is much lower than previously thought, and raise questions about the connection between RNF43 and disease. The results highlight the complexity of genetic counseling in RNF43 positive families- particularly in families without polyposis. Further research is needed to elucidate the role of RNF43 in the risk of SPS and CRC.
Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal vascular dysplasia characterized by the presence of mucocutaneous telangiectasia and arteriovenous malformations in solid organs. The Curaçao criteria and/or de...Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal vascular dysplasia characterized by the presence of mucocutaneous telangiectasia and arteriovenous malformations in solid organs. The Curaçao criteria and/or detection of ALK1, ENG, and SMAD4 gene mutations are used for diagnosis. Juvenile Polyposis Syndrome (JPS) is diagnosed according to the number and localization of juvenile polyps, and family history of JPS. Both entities have a low prevalence. Mutation of SMAD4 leads to a combined syndrome of these two conditions called HHT-JPS Overlap Syndrome. We aim to describe the clinical characteristics associated with this condition focusing on long term follow up and review of the literature. A cross-sectional descriptive study of HHT-JPS cases from an HHT Institutional Registry was designed. Patients were eligible for this case series if they fulfilled both HHT and JPS diagnostic criteria and/or mutation on SMAD4. A comprehensive review was conducted on the clinical phenotype associated with HHT and its gastrointestinal involvement. Fourteen patients from eleven families in 788 previously HHT-diagnosed patients met the inclusion criteria. The ages ranged between 25 and 70 years old and 12 were females. In addition to the typical signs/symptoms of HHT, two distinct phenotypes were observed. Nine patients predominantly exhibited initially upper, while five showed predominantly initially lower gastrointestinal involvement. Numerous musculoskeletal and cardiovascular anomalies were also identified. The observed phenotypic diversity, particularly in gastrointestinal involvement, underscores the need for tailored clinical approaches. Comprehensive assessments identified associated musculoskeletal and cardiovascular anomalies, emphasizing the systemic nature of HHT-JPS.
The discovery of "mismatch repair deficient (MMRd)-crypt foci" in non-neoplastic intestinal mucosa in Lynch syndrome (LS) has significantly enhanced our understanding of how tumors and tumor immunity form and evolve in L...The discovery of "mismatch repair deficient (MMRd)-crypt foci" in non-neoplastic intestinal mucosa in Lynch syndrome (LS) has significantly enhanced our understanding of how tumors and tumor immunity form and evolve in LS. In this study, we report the frequent presence of "mismatch repair proficient (MMRp)-crypt foci" in both non-neoplastic and neoplastic intestinal mucosa in a patient with constitutional MMR deficiency (CMMRD), who carried a germline MSH6 pathogenic variant (c.3261dupC) in trans with an MSH6 likely pathogenic variant (c.3724_3726del) and whose tissues were otherwise deficient in MMR globally. The MMRp-crypts occurred at a rate of 1.1/100 crypts in non-neoplastic intestinal mucosa and were readily discernible in adenomas > 1 cm. Sequencing analysis revealed normalization of the MSH6c.3261dupC variant in MMRp-adenoma crypts, indicating reverse frameshifting of the exon 5 C8 microsatellite. Interestingly but not surprisingly, the MMRp-adenoma crypts remained microsatellite-instability-high (MSI-H), and shared oncogenic APC mutations with the background MMRd-adenoma. Contrasting with MSH6-CMMRD, no PMS2-CMMRD individuals (0/5) harbored MMRp-crypts. In conclusion, our study documents distinct MMRp-crypts in MSH6-CMMRD, a phenomenon in keeping with MSH6 being a frequent target of MSI-H due to its coding microsatellite and suggesting that MSH6-CMMRD can potentially serve as a unique model system to further our understanding of MSH6's role in MSI-H tumor formation and evolution. Our findings also bear diagnostic implications; when using MMR immunohistochemistry as an ancillary tool in detecting CMMRD, awareness of these MMRp crypts can help avoid diagnostic pitfalls.
While universal tumor testing for Lynch Syndrome (LS) is recommended in all new diagnoses of colorectal cancer (CC) and endometrial cancer (EC), the cost and availability of this test in low-resource settings poses chall...While universal tumor testing for Lynch Syndrome (LS) is recommended in all new diagnoses of colorectal cancer (CC) and endometrial cancer (EC), the cost and availability of this test in low-resource settings poses challenges. The PREdiction Model for gene Mutations (PREMM) is a clinical algorithm designed to assess the risk of an individual carrying estimates one's risk of carrying a LS mutation. This study aims to assess the feasibility of using PREMM to screen for LS risk in Guatemala. This cross-sectional pilot study enrolled 50 patients with colorectal or endometrial cancer receiving treatment at LIGA-INCAN, a cancer hospital in Guatemala City, between June 2022-July 2022. Patients were contacted by phone and administered the PREMM survey, followed by an additional feasibility questionnaire. Of the 50 participants, 62% of patients had a PREMM predicted probability of ≥ 2.5%, the threshold above which genetic testing is recommended. Almost all patients found the survey easy to complete (98%), were able to easily recall personal (90%) and family (88%) medical history, understood its purpose (94%), and reported an interest in (96%) and ability to (98%) act on the results if applicable. Our study shows the role of the PREMM as a feasible tool for identifying individuals at risk of carrying mutations associated with LS in this low-resource setting. By implementing the PREMM model, high risk individuals can be identified early, enabling timely interventions and improving outcomes in this at-risk population.
Howard Sharp KM, Clark ME, Jurbergs N
… +13 more, Ouma A, Harrison L, Taylor L, Hamilton K, McGee RB, Nuccio R, Hines-Dowell S, Gattuso JS, Pritchard M, Mandrell B, Tercyak KP, Johnson LM, Nichols KE
Germline genomic sequencing is increasingly integrated into pediatric cancer care, with pathogenic cancer-predisposing variants identified among 5-18% of affected children and variants of uncertain significance (VUS) in...Germline genomic sequencing is increasingly integrated into pediatric cancer care, with pathogenic cancer-predisposing variants identified among 5-18% of affected children and variants of uncertain significance (VUS) in up to 70%. Given the potential medical implications for children and their families, parents' psychosocial responses to learning results are important to understand. Parents of children with cancer who learned their children's germline pathogenic or VUS results following paired tumor and germline genomic sequencing described their cognitive and affective responses to results in an open-ended write-in question after disclosure (M = 10 months post-disclosure; range = 1-28). Responses were coded and categorized using content analysis, then compared across results using chi-square and Fisher's exact test. Parents of children with pathogenic (n = 9), VUS (n = 52), and pathogenic plus VUS results (n = 9) described negative emotions, positive reactions, mixed emotions (i.e., positive and negative emotions), and neutral reactions. Negative emotions were described significantly more frequently with pathogenic results than VUS only (χ = 5.19; p = .02), with peace of mind and empowerment only described for those with VUS. Parents also described approach(es) to coping (e.g., faith, plan of action) and reactions specific to the uncertainty of VUS (e.g., disappointment at no explanation for cancer etiology). A subset with VUS described decreasing worry/distress with increased understanding of results, whereas others displayed misconceptions regarding VUS. Screening for emotional adjustment is warranted for parents of children with cancer receiving pathogenic germline results, and screening for understanding is warranted with VUS. Findings highlight the importance of pre-and posttest genetic counseling.
To determine the preoperative detection of signet ring cancer cells (SRC) on upper endoscopy (EGD) in patients with CDH1 pathogenic variant (PV) undergoing gastrectomy. To evaluate the development of advanced diffuse gas...To determine the preoperative detection of signet ring cancer cells (SRC) on upper endoscopy (EGD) in patients with CDH1 pathogenic variant (PV) undergoing gastrectomy. To evaluate the development of advanced diffuse gastric cancer (DGC) in patients choosing surveillance. Guidelines recommend prophylactic total gastrectomy (pTG) in CDH1 PV carriers with family history of DGC between 18 and 40 years. Annual EGD with biopsies according to established protocols is recommended in carriers with no SRC and no family history of DGC, with consideration of pTG. Retrospective analysis of asymptomatic patients with CDH1 PVs with ≥ 1 surveillance EGD. Outcomes included pre-operative EGD detection of SRC, surgical stage, and progression to advanced DGC in those electing surveillance with EGD. 48 patients with CDH1 PVs who had ≥ 1 EGD were included. 24/ 48 (50%) underwent gastrectomy, including pTG in 7 patients. SRCC were detected on gastrectomy specimen in 21/24 (87.5%). SRCs were identified by EGD in 17/21 patients who had SRCC on gastrectomy specimens (sensitivity 81%, 17/21). All cancers were stage pT1a. The remaining 17 patients (50% with a family history of gastric cancer) continue in annual EGD surveillance with a median follow-up of 34.6 months. No SRCC or advanced DGC have been diagnosed. No CDH1 PV carriers without SRCC on random biopsies followed in an endoscopic program developed advanced DGC over a median follow up of 3 years. In the short term, EGD surveillance might be a safe alternative to immediate pTG in experienced hands in referral centers.
Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with germline pathogenic/likely pathogenic variants in TP53. Genotype-phenotype correlations are progressively being characterized in LFS with cer...Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with germline pathogenic/likely pathogenic variants in TP53. Genotype-phenotype correlations are progressively being characterized in LFS with certain TP53 variants associated with attenuated penetrance and phenotypes. We report on a family harboring a TP53 p.R181H variant presenting with a restricted cancer phenotype in adulthood. The proband was a female with breast cancer at the age of 71 years who had three first degree relatives also diagnosed with breast cancer after the age of 40 years (mother, two sisters). Of the nine individuals harboring the variant (6 genetically confirmed, 3 obligate heterozygous), six have not developed malignancies at this time (age range: 36-42). No childhood-onset cancers were reported in this family. A concomitant literature review identified 51 additional individuals harboring the p.R181H variant in TP53, presenting a tumor phenotype dominated by breast cancer. Rare occurrences of other adult-onset cancers (prostate, colorectal and thyroid) and only few childhood onset cancer were documented. These observations are consistent with functional analysis showing that p.R181H retains partial p53 function and suggesting possible reduced cancer penetrance, particularly in the pediatric setting.
Bloom syndrome (BS) is a rare genetic disorder caused by biallelic inactivation of the BLM gene, which usually manifests in childhood by significant growth retardation, immune deficiency, characteristic skin lesions, can...Bloom syndrome (BS) is a rare genetic disorder caused by biallelic inactivation of the BLM gene, which usually manifests in childhood by significant growth retardation, immune deficiency, characteristic skin lesions, cancer predisposition and other distinguishable disease features. To our knowledge, all prior instances of BS have been identified via intentional analysis of patients with clinical suspicion for this disease or DNA testing of members of affected pedigrees. We describe an incidental finding of BS, which occurred upon routine germline DNA analysis of consecutive breast cancer patients. The person with the biallelic pathogenic BLM c.1642C>T (p.Gln548Ter) variant remained clinically healthy for 38 years until she developed breast cancer. Detailed examination of this woman, which was carried out after the genetic diagnosis, revealed mild features of BS. A sister chromatid exchange (SCE) test confirmed the presence of this syndrome. The tumor exhibited triple-negative receptor status, a high proliferation rate, a low tumor mutation burden (TMB), and a moderate level of chromosomal instability (homologous recombination deficiency (HRD) score = 29). The patient showed normal tolerability to radiotherapy and several regimens of cytotoxic therapy. Thus, some BS patients may remain undiagnosed due to the mild phenotype of their disease. BLM should be incorporated in gene panels utilized for germline DNA testing of cancer patients.
Non-small cell lung cancer is the most common cause of cancer death globally. When apparent incidental pathogenic germline variants (PGVs) are uncovered with routine next generation sequencing (NGS) of NSCLCs, germline t...Non-small cell lung cancer is the most common cause of cancer death globally. When apparent incidental pathogenic germline variants (PGVs) are uncovered with routine next generation sequencing (NGS) of NSCLCs, germline testing (GT) is recommended to confirm that PGV. Because it is far more common that an uncovered tumor TP53 variant is related to a somatic event than an incidental PGV, however, GT for Li Fraumeni syndrome (LFS) is not recommended based solely on uncovering a NSCLC TP53 variant. Because nearly all tumor EGFR variants are also somatic in origin, GT is not recommended based solely on uncovering a tumor EGFR variant.However, there is evidence that patients with coexisting NSCLC variants in both EGFR and TP53 have significant likelihoods of having LFS. For patients with LFS, there are recommended measures for prevention and early detection of LFS-associated cancers and cascade GT of relatives for LFS. Although co-existing genetic variants in NSCLC are not currently used as a biomarker for GT to identify patients with PGVs, given the evidence reviewed here, select patients with NSCLCs that harbor this dual biomarker (i.e., co-existing TP53/EGFR variants) might reasonably be considered for GT for LFS.
BACKGROUND AND STUDY AIMS: Lynch syndrome (LS) is a hereditary autosomal dominant condition, with an increased lifetime risk of developing malignancies including colorectal cancer (CRC). Current guidelines differ in reco...BACKGROUND AND STUDY AIMS: Lynch syndrome (LS) is a hereditary autosomal dominant condition, with an increased lifetime risk of developing malignancies including colorectal cancer (CRC). Current guidelines differ in recommended colonoscopy-surveillance intervals from 1 to 2 years. Although colonoscopy is considered a safe procedure, there are risks of severe adverse events (SAEs), such as perforation and bleeding, as well as adverse events (AEs), such as abdominal discomfort and post-colonoscopy gastrointestinal infections. Colonoscopy-related bleeding and perforation rates have been reported 0.17% and 0.11%, respectively. However, there are insufficient data regarding complications of colonoscopy-surveillance for LS patients. This study aims to investigate the risk of AEs among LS patients during colonoscopy in the Stockholm region. PATIENTS AND METHODS: This retrospective cohort study includes 351 LS patients undergoing endoscopic surveillance at the Karolinska University Hospital, August 1989 - April 2021. Data from endoscopic surveillance colonoscopies were extracted from patients' medical records. RESULTS: Of 1873 endoscopies in 351 LS patients, 12 complications (AEs) were documented within 30 days (0.64%) and with a total of 3 bleedings (SAEs, 0.16%). No perforations were identified. CONCLUSION: Colonoscopy surveillance for LS patients shows a comparatively low risk of AEs per-examination. Colonoscopy complications per-patient, including both SAEs and AEs, show a significantly higher risk. Colonoscopy complications only including SAEs, show a comparatively low risk. Understanding the lifetime risk of surveillance-related colonoscopy complications is important when designing targeted surveillance programmes.
Lynch syndrome predisposes to a high risk of colorectal cancer and colonoscopy remains the primary preventive strategy. The prevention of colorectal cancer through colonoscopy relies on identifying and removing adenomas,...Lynch syndrome predisposes to a high risk of colorectal cancer and colonoscopy remains the primary preventive strategy. The prevention of colorectal cancer through colonoscopy relies on identifying and removing adenomas, the main precursor lesion. Nevertheless, colonoscopy is not an optimal strategy since post-colonoscopy colorectal cancer remains an important issue. In continuation of a 2021 journal review, the present article seeks to offer an updated perspective by examining relevant articles from the past 3 years. We place recent findings in the context of existing guidelines, with a specific focus on colonoscopy surveillance. Key aspects explored include colonoscopy quality standards, timing of initiation, and surveillance intervals. Our review provides a comprehensive analysis of adenoma-related insights in Lynch syndrome, delving into emerging technologies like virtual chromoendoscopy and artificial intelligence-assisted endoscopy. This review aims to contribute valuable insights into the topic of colonoscopy surveillance in Lynch syndrome.
BACKGROUND: Familial adenomatous polyposis (FAP) predisposes individuals to duodenal adenomas. This study describes the histopathological features of endoscopic and surgical specimens from the duodenum, as well as genoty...BACKGROUND: Familial adenomatous polyposis (FAP) predisposes individuals to duodenal adenomas. This study describes the histopathological features of endoscopic and surgical specimens from the duodenum, as well as genotype-phenotype associations. METHODS: All known FAP patients were included from the Danish Polyposis Register. FAP patients were defined as having more than 100 cumulative colorectal adenomas and/or having a known germline pathogenic variant in the APC gene. Endoscopic procedures, histopathology, and genetics were evaluated. RESULTS: Of 500 FAP patients, 70.6% underwent esophagogastroduodenoscopy (EGD) at least once. Of these, 59.2% presented with detectable duodenal adenomas. The most severe morphology was tubular in 62.7% patients, tubulovillous in 25.4%, and villous in 12.0%, while the most severe dysplasia was low-grade in 67.5% patients, high-grade in 25.4%, and 6.7% had adenocarcinoma. In 6.2% of FAP patients, duodenal resection was recommended, including 29% with duodenal adenocarcinoma. The risk of duodenal surgery was 1.31 per 1,000 person-years (median age: 53 years). The predominant reason for surgery was extensive polyposis (67.7%). Of the patients who underwent duodenal resection, a median of six (IQR: 4-8) EGDs were performed within five years prior to surgery, but 67.6% and 83.9% never underwent a duodenal polypectomy or endoscopic mucosa resection, respectively. Of note, seventeen of 500 patients (3.4%) developed duodenal adenocarcinoma, of which 47% were advanced at diagnosis. Genetic evaluations revealed various pathogenic variants in the APC gene, with no strong genotype-phenotype association. CONCLUSIONS: The prevalence of duodenal adenomas and cancer in FAP warrants vigilant endoscopic surveillance. Nevertheless, the need for duodenal surgery persists and should together with endoscopic practice be monitored in national registers.
Biallelic germline pathogenic variants in one of the four mismatch repair genes (MSH2, MSH6, MLH1 and PMS2) cause a very rare, highly penetrant, childhood-onset cancer syndrome, called constitutional mismatch repair defi...Biallelic germline pathogenic variants in one of the four mismatch repair genes (MSH2, MSH6, MLH1 and PMS2) cause a very rare, highly penetrant, childhood-onset cancer syndrome, called constitutional mismatch repair deficiency (CMMRD). The European consortium "Care for CMMRD" (C4CMMRD) was founded in Paris in 2013 to facilitate international collaboration and improve our knowledge of this rare cancer predisposition syndrome. Following initial publications on diagnostic criteria and surveillance guidelines for CMMRD, several partners collaborating within the C4CMMRD consortium have worked on and published numerous CMMRD-related clinical and biological projects. Since its formation, the C4CMMRD consortium held meetings every 1-2 years (except in 2020 and 2021 due to the Covid 19 pandemic). The sixth C4CMMRD meeting was held in Paris in November 2022, and brought together 42 participants from nine countries involved in various fields of CMMRD healthcare. The aim was to update members on the latest results and developments from ongoing research, and to discuss and initiate new study proposals. As previously done for the fifth meeting of the C4CMMRD group, this report summarizes data presented at this meeting.
Family-history assessment can identify individuals above population-risk for cancer to enable targeted Screening, Prevention and Early Detection (SPED). The online patient-facing cancer Family History Questionnaire Servi...Family-history assessment can identify individuals above population-risk for cancer to enable targeted Screening, Prevention and Early Detection (SPED). The online patient-facing cancer Family History Questionnaire Service (cFHQS) is a digitalised, resource efficient tool for family history data capture to facilitate this. The capturing of digital data from cFHQS allows for data interrogation of patients referred to Clinical Genetics for the purposes of service improvement. Digital data from 4,044 cFHQS respondents over a three-year period was collected and interrogated with respect to the number and type of familial tumour diagnoses to enable service improvement and streamlining of referral pathways. 81% of colorectal and 71% of breast screening assessments were population- or moderate-risk. Most patients who completed cFHQS reported more than one diagnosis of cancer/tumour/polyps in their family. 2.5% of family history assessment patients had a second indication that required assessment that would have been missed if single tumour type assessment was undertaken. Implementation of an innovative, digital family history data collection pathway has allowed large scale interrogation of referral patterns and assessment outcomes to enable service development. The high volume of inappropriate referrals to Clinical Genetics for population and moderate risk patients highlighted the need for dedicated secondary care pathway provision for these patients. The use of cFHQS streamlined family history assessment allows for redistribution of resources to improve equity and access to genetic cancer risk assessment.
Epithelial ovarian cancer (EOC) is the most lethal type of gynaecological cancer, due to lack of effective screening possibilities and because the disease tends to metastasize before onset of symptoms. Women with an incr...Epithelial ovarian cancer (EOC) is the most lethal type of gynaecological cancer, due to lack of effective screening possibilities and because the disease tends to metastasize before onset of symptoms. Women with an increased inherited risk for EOC are advised to undergo a risk-reducing salpingo-oophorectomy (RRSO), which decreases their EOC risk by 96% when performed within guideline ages. However, it also induces premature menopause, which has harmful consequences. There is compelling evidence that the majority of EOCs originate in the fallopian tube. Therefore, a risk-reducing salpingectomy with delayed oophorectomy (RRS with DO) has gained interest as an alternative strategy. Previous studies have shown that this alternative strategy has a positive effect on menopause-related quality of life and sexual health when compared to the standard RRSO. It is hypothesized that the alternative strategy is non-inferior to the standard RRSO with respect to oncological safety (EOC incidence). Three prospective studies are currently including patients to compare the safety and/or quality of life of the two distinct strategies. In this article we discuss the background, opportunities, and challenges of the current and alternative strategy.
Fanconi anemia (FA) is an inherited bone marrow failure syndrome (IBMFS) characterized by pathogenic variants in the FA/BRCA DNA repair pathway genes. Individuals with FA have an elevated risk of developing myelodysplast...Fanconi anemia (FA) is an inherited bone marrow failure syndrome (IBMFS) characterized by pathogenic variants in the FA/BRCA DNA repair pathway genes. Individuals with FA have an elevated risk of developing myelodysplastic syndrome, acute myeloid leukemia, and solid tumors. Hematopoietic cell transplantation (HCT) is the most effective treatment for FA related bone marrow failure but can increase the risk of cancer development. Information on benign tumors and NMSC is lacking in patients with FA. Our objective was to characterize patients with FA enrolled in the National Cancer Institute IBMFS Study who have experienced non-melanoma skin cancers (NMSC) and/or benign tumors (BT). A total of 200 patients diagnosed with FA were enrolled in the Institutional Review Board approved study "Etiologic Investigation of Cancer Susceptibility in IBMFS: A Natural History Study" (NCT00027274). Through medical records review, we identified 30 patients with at least one NMSC, either squamous or basal cell carcinoma, or benign tumor. The remaining 170 patients comprised the control group. Out of 200 patients, 12 had NMSC, 25 had benign tumors, with an age range of 11-64 and 0-56 years, respectively. The median age at HCT was 30.5 years for NMSC patients, 9 years for benign tumor patients, and 9.1 years for controls. The most common genotype observed was FANCA, followed by FANCC and FANCI. Benign tumors spanned diverse anatomical locations. Early onset NMSC in patients with FA compared to the general population emphasizes the need for consistent monitoring in patients with FA, while the diverse anatomical locations of benign tumors underscore the importance of comprehensive surveillance for timely interventions in managing symptomatology and heightened cancer risk.
PMS2, a Lynch Syndrome gene, presents challenges in genetic testing due to the existence of multiple pseudogenes. This study aims to describe a series of cases harboring a variant in the PMS2CL pseudogene that has been i...PMS2, a Lynch Syndrome gene, presents challenges in genetic testing due to the existence of multiple pseudogenes. This study aims to describe a series of cases harboring a variant in the PMS2CL pseudogene that has been incorrectly assigned to PMS2 with different nomenclatures. We reviewed data from 647 Brazilian patients who underwent multigene genetic testing at a single center to identify those harboring the PMS2 V1:c.2186_2187delTC or V2:c.2182_2184delACTinsG variants, allegedly located at PMS2 exon 13. Gene-specific PCR and transcript sequencing was performed. Among the 647 individuals, 1.8% (12) carried the investigated variants, with variant allele frequencies ranging from 15 to 34%. By visually inspecting the alignments, we confirmed that both V1 and V2 represented the same variant and through gene-specific PCR and PMS2 transcript analysis, we demonstrated that V1/V2 is actually located in the PMS2CL pseudogene. Genomic databases (ExAC and gnomAD) report an incidence of 2.5 - 5.3% of this variant in the African population. Currently, V1 is classified as "uncertain significance" and V2 as "conflicting" in ClinVar, with several laboratories classifying them as "pathogenic". We identified a frequent African PMS2CL variant in the Brazilian population that is misclassified as a PMS2 variant. It is likely that V1/V2 have been erroneously assigned to PMS2 in several manuscripts and by clinical laboratories, underscoring a disparity-induced matter. Considering the limitations of short-read NGS differentiating between certain regions of PMS2 and PMS2CL, using complementary methodologies is imperative to provide an accurate diagnosis.
van Riel L, Kets CM, van Hest LP
… +9 more, Menko FH, Boerrigter BG, Franken SM, Wolthuis RMF, Dubbink HJ, Zondervan PJ, van Moorselaar RJA, Houweling AC, van de Beek I