Submissions for variant NM_000179.3(MSH6):c.1847C>G (p.Ser616Cys)

dbSNP: rs772363120

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210205	SCV000266203	uncertain significance	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Invitae	RCV000524121	SCV000283732	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000410099	SCV000489415	uncertain significance	Lynch syndrome 5	2016-10-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000575424	SCV000662410	likely benign	Hereditary cancer-predisposing syndrome	2018-10-08	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.
Color Diagnostics, LLC DBA Color Health	RCV000575424	SCV000908382	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-15	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cysteine at codon 616 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with prostate, kidney, and thyroid cancers (PMID: 26845104). This variant has been identified in 15/276794 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284178	SCV001469819	uncertain significance	not provided	2023-08-01	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with thyroid, prostate, and kidney cancers (PMID: 26845104 (2016)). In a breast cancer association study, this variant was reported in an individual with breast cancer as well as in an unaffected control individual (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MSH6)). The frequency of this variant in the general population, 0.00042 (15/35422 chromosomes in Latino/Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000410099	SCV001737487	uncertain significance	Lynch syndrome 5	2021-05-06	criteria provided, single submitter	clinical testing	The MSH6 c.1847C>G (p.Ser616Cys) missense change has a maximum subpopulation frequency of 0.042% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/2-48026969-C-G?dataset=gnomad_r2_1). Six of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in an individual with a personal history of thyroid, prostate, and kidney cancers (PMID: 26845104). To our knowledge, this variant has not been reported in individuals with Lynch syndrome or CMMRD. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.
GeneDx	RCV001284178	SCV002820632	uncertain significance	not provided	2023-09-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with a personal and family history of renal, prostate, and other cancers (Shirts et al., 2016); This variant is associated with the following publications: (PMID: 17531815, 21120944, 26845104)
Myriad Genetics, Inc.	RCV000410099	SCV004018437	likely benign	Lynch syndrome 5	2023-03-27	criteria provided, single submitter	clinical testing	This variant is considered likely benign. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479062	SCV004222654	uncertain significance	not specified	2023-11-15	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1847C>G (p.Ser616Cys) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain (IPR007860) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 250646 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MSH6 causing Lynch Syndrome (5.6e-05 vs 0.00014), allowing no conclusion about variant significance. c.1847C>G has been reported in the literature in settings of multigene panel setting in at least one individual affected with thyroid, prostate, kidney cancers, reported as a VUS (e.g. Shirts_2016) or with an unspecified cancer (e.g. Li_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=6) and likely benign (n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV000210205	SCV004835434	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cysteine at codon 616 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with prostate, kidney, and thyroid cancers (PMID: 26845104). This variant has been identified in 15/276794 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.