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

gnomAD frequency: 0.00013  dbSNP: rs63750664

Total submissions: 20

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 1	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	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524208	SCV000254329	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-25	criteria provided, single submitter	clinical testing
Counsyl	RCV000412384	SCV000487828	uncertain significance	Lynch syndrome 5	2015-11-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	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	2023-04-20	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 9.8e-05 in 244188 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), 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 tumors belonging to the Lynch syndrome spectrum (e.g. Charames_2000, Nilbert_2009, Hinrichsen_2013, Grant_2015, Frolova_2015, Gordon_2019, Li_2020, Svensson_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. In vitro studies reported experimental evidence evaluating an impact on protein function, in which MMR activity of the variant protein was 50%-90% of wild-type activity (Drost_2011, Drost_2020). Ten other submitters, including an expert panel (InSiGHT), have provided clinical-significance assessments for this variant in ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant as VUS (n=3), likely benign (n=6, including the expert panel) or benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Laboratory for Molecular Medicine, Mass General Brigham 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 Laboratory Services, Illumina	RCV000412384	SCV001299751	uncertain significance	Lynch syndrome 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.
Sema4, Sema4	RCV000115435	SCV002536331	likely benign	Hereditary cancer-predisposing syndrome	2021-03-25	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000254665	SCV002552265	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000412384	SCV004018951	benign	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.
CeGaT Center for Human Genetics Tuebingen	RCV001529757	SCV005330197	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	MSH6: BP1, BS1:Supporting, BS3:Supporting
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
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001529757	SCV002037018	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739338	SCV005351795	likely benign	MSH6-related disorder	2024-07-05	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).