Submissions for variant NM_000179.3(MSH6):c.942C>G (p.Ser314Arg)

gnomAD frequency: 0.00011  dbSNP: rs150440246

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219163	SCV000273064	likely benign	Hereditary cancer-predisposing syndrome	2022-08-16	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	RCV000475100	SCV000551219	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000478810	SCV000569371	likely benign	not provided	2020-03-25	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27443514, 28135145)
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659889	SCV000781785	likely benign	Lynch syndrome 5	2016-11-01	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000761132	SCV000891048	uncertain significance	Lynch syndrome	2020-10-15	criteria provided, single submitter	clinical testing	The MSH6 c.942C>G (p.Ser314Arg) missense change has a maximum subpopulation frequency of 0.056% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/2-48026064-C-G). Six of seven in silico tools predict a benign effect of this variant on protein function (BP4), but these predictions have not been confirmed by functional studies. This variant has been reported in individuals with colorectal cancer (PMID: 28135145) and endometrial cancer (PMID: 27443514). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.
Color Diagnostics, LLC DBA Color Health	RCV000219163	SCV000911372	likely benign	Hereditary cancer-predisposing syndrome	2016-04-11	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000219163	SCV002536368	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-21	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265689	SCV002547891	uncertain significance	not specified	2022-05-02	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.942C>G (p.Ser314Arg) 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 4.8e-05 in 251294 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MSH6 causing Prostate Cancer (4.8e-05 vs 6.3e-05), allowing no conclusion about variant significance. c.942C>G has been reported in the literature as a germline Benign/VUS variant in settings of multigene panel testing among individuals with a variety of cancers such as ALL, Endometrial and Colorectal Cancer (example, Zhang_2015, Ring_2016, Yurgelun_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome and related cancers. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Likely Benign, n=3; VUS, n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV000761132	SCV004834923	likely benign	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739607	SCV005360105	uncertain significance	MSH6-related disorder	2024-06-14	no assertion criteria provided	clinical testing	The MSH6 c.942C>G variant is predicted to result in the amino acid substitution p.Ser314Arg. This variant was identified in individuals with endometrial, colorectal, and breast cancer (Table S2, Ring et al. 2016. PubMed ID: 27443514; Table A4, Yurgelun et al. 2017. PubMed ID: 28135145; Table S3, de Oliveira et al. 2022. PubMed ID: 35534704). This variant is reported in 0.056% of alleles in individuals of African descent in gnomAD and has conflicting interpretations in ClinVar regarding its pathogenicity including likely benign and uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/229741/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.