ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3259C>T (p.Pro1087Ser) (rs63750998)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131245 SCV000186203 likely benign Hereditary cancer-predisposing syndrome 2018-07-18 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Does not segregate with disease in family study (genes with incomplete penetrance);In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s);Other data supporting benign classification
GeneDx RCV000514075 SCV000211319 uncertain significance not provided 2018-06-14 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3259C>T at the cDNA level, p.Pro1087Ser (P1087S) at the protein level, and results in the change of a Proline to a Serine (CCC>TCC). MSH6 Pro1087Ser has been identified in ovarian and colorectal cancer patients, and three of four of the colon tumors in these individuals were MSI-L (Ohmiya 2001, Domingo 2005, Niessen 2006, Okkels 2012, Pal 2012). In one colorectal cancer case, tumor immunohistochemistry was normal and a second missense variant, MUTYH Arg295Cys, was also identified (Niessen 2006). An in vitro cell free mismatch repair complementation assay demonstrated 88% repair efficiency, suggesting MSH6 Pro1087Ser is not pathogenic (Drost 2010). MSH6 Pro1087Ser was observed at an allele frequency of 0.03% (32/126,702) in individuals of European ancestry in large population cohorts (Lek 2016). MSH6 Pro1087Ser is located within the ATPase domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the currently available evidence, it is unclear whether MSH6 Pro1087Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV001079820 SCV000254310 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-04 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000212678 SCV000539706 uncertain significance not specified 2016-06-16 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: 5 VUS (including expert panel - no new evidence since expert classification)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000514075 SCV000601567 uncertain significance not provided 2019-11-08 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000514075 SCV000610412 uncertain significance not provided 2017-08-25 criteria provided, single submitter clinical testing
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000131245 SCV000679731 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-23 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764429 SCV000895486 uncertain significance Endometrial carcinoma; Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 5 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131245 SCV000902789 likely benign Hereditary cancer-predisposing syndrome 2016-01-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212678 SCV000917755 likely benign not specified 2018-04-06 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3259C>T (p.Pro1087Ser) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant; although an in silico study predicted no impact on protein function (Terui 2013). One publication reported experimental evidence, demonstrating in an in vitro mismatch repair assay 88% repair efficiency compared to the wild type; suggesting no damaging effect for this variant. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.76 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00025 vs. 0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.3259C>T has been reported in the literature in individuals affected with colorectal carcinoma (Ohmiya 2001, Domingo 2005, Niessen 2006, Okkels 2012), ovarian cancer (Pal 2012) and pancreatic ductal adenocarcinoma (Hu 2016). However, these reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Moreover, in 3 of the reported colorectal cancer cases, tumor immunohistochemistry was normal, and in 2 of these cases microsatellite instability (MSI) was reported to be low. A recent publication assessing associated cancer risks of several variants in the Icelandic population, suggests that the variant is benign based on the population frequency and the low odds ratio for colorectal cancer (Haraldsdottir 2017). Furthermore, in this study, this variant was observed among 2 patients with promoter hypermethylation of MLH1 and 1 patient with absent MLH1/PMS2 on tumor IHC, suggestive of sporadic (MLH1 hypermethylation) or an alternate molecular basis of disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and reported the variant with conflicting assessments (2 calling it Likely Benign and 4 calling it a VUS). Based on the evidence outlined above, the variant was classified as likely benign.
Institute of Human Genetics, University of Leipzig Medical Center RCV001262368 SCV001440208 uncertain significance Breast carcinoma 2019-01-01 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148653 SCV000190368 uncertain significance Ovarian cancer 2014-06-01 no assertion criteria provided research

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