ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.59C>T (p.Ala20Val) (rs63750664)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075009 SCV000108229 likely benign Lynch syndrome I 2018-06-13 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability < 0.05 (0.028)
GeneDx RCV000254665 SCV000149344 likely benign not specified 2017-11-29 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000115435 SCV000184016 likely benign Hereditary cancer-predisposing syndrome 2018-12-06 criteria provided, single submitter clinical testing In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s)
Invitae RCV000524208 SCV000254329 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-03 criteria provided, single submitter clinical testing
Counsyl RCV000412384 SCV000487828 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2015-11-24 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115435 SCV000690451 likely benign Hereditary cancer-predisposing syndrome 2014-12-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000254665 SCV000695918 likely benign not specified 2020-08-31 criteria provided, single submitter clinical testing Variant summary: MSH6 c.59C>T (p.Ala20Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 275540 control chromosomes, predominantly at a frequency of 0.00019 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.34 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.59C>T has been reported in the literature in individuals affected with colorectal cancer/pancreatic cancer/Lynch Syndrome (Nilbert_2009, Hinrichsen_2013, Grant_2015, Frolova_2015, Charames_2000, Gordon_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. One co-occurrence with another pathogenic variant has been reported internally (BRCA2 c.8677C>T, p.Gln2893X), providing supporting evidence for a benign role. In vitro studies report experimental evidence evaluating an impact on protein function in which MMR activity in a cell free assay was 50%-90% of wild-type activity (Drost_2011, Drost_2020). Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (3x) and likely benign (4x). Based on the evidence outlined above, the variant was classified as likely benign.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000254665 SCV000712602 uncertain significance not specified 2017-02-20 criteria provided, single submitter clinical testing The p.Ala20Val variant in MSH6 has been reported in 3 individuals with Lynch syn drome-associated cancers (Charames 2000, Nilbert 2009) and has also been reporte d in ClinVar (Variation ID 89540). In vitro functional studies provide some evid ence that the p.Ala20Val variant may not impact protein function (Drost 2012). H owever, these types of assays may not accurately represent biological function. This variant has also been identified in 7/62168 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs6375 0664). Computational prediction tools and conservation analysis suggest that the p.Ala20Val variant may not impact the protein, though this information is not p redictive enough to rule out pathogenicity. In summary, the clinical significanc e of the p.Ala20Val variant is uncertain.
Illumina Clinical Services Laboratory,Illumina RCV000412384 SCV001299751 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CSER _CC_NCGL, University of Washington RCV000148647 SCV000190362 uncertain significance Colorectal / endometrial cancer 2014-06-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353783 SCV000592562 benign Carcinoma of colon no assertion criteria provided clinical testing The p.Ala20Val variant was identified in 3 of 2290 proband chromosomes (frequency: 0.001) from individuals or families with colorectal cancer (Charames 2000, Nilbert 2009, Wasielewski 2009) and was present in 1 of 332 control chromosomes (frequency: 0.003) from healthy individuals (Wasielewski 2009). The variant was also identified in dbSNP (ID: rs63750664), with a minor allele frequency of 0.0002 (1000 Genomes Project), NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, MutDB, “Mismatch Repair Genes Variant Database”, “InSiGHT Colon Cancer Database”, the ClinVar database (classified with uncertain significance by InSiGHT and Ambry Genetics; classified as likely benign by GeneDx), and UMD (1X as a likely neutral variant). The variant was identified by the Exome Variant Server project in 3 of 8566 European American alleles (frequency: 0.0003), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease.The p.Ala20 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. The p.Ala20Val variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing, although this is not very predictive of pathogenicity. A study by Charames (2000) suggested this alteration result in a significant change in amino acid polarity occurring outside of the MSH6 domains known to interact with MSH2.However, three functional studies have suggested the variant has no impact on MSH6 gene and has neutral functional effect (Ali 2012, Drost 2012, Terui 2013). In addition, this variant was identified in one individual by our laboratory as co-occuring with a pathogenic variant in MSH6 (c.3932_3935dup, p.Ile1313SerfsX7), increasing the likelihood this variant does not have clinical significance. In summary, based on the above information, this variant is classified as benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000254665 SCV000691915 uncertain significance not specified no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV001529757 SCV001743775 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV001529757 SCV001807447 likely benign not provided no assertion criteria provided clinical testing

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