ClinVar Miner

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

gnomAD frequency: 0.00011  dbSNP: rs150440246
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Total submissions: 9
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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.
Invitae 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

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