Submissions for variant NM_000179.3(MSH6):c.831A>C (p.Glu277Asp)

gnomAD frequency: 0.00006  dbSNP: rs374486449

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235181	SCV000211263	uncertain significance	not provided	2023-09-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer (Tung et al., 2015; Yehia et al., 2018; Bhai et al., 2021); This variant is associated with the following publications: (PMID: 23621914, 29684080, 21437237, 25186627, 34326862)
Ambry Genetics	RCV000160656	SCV000217992	likely benign	Hereditary cancer-predisposing syndrome	2022-08-18	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	RCV000196039	SCV000254334	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-11	criteria provided, single submitter	clinical testing
Counsyl	RCV000411901	SCV000488512	uncertain significance	Lynch syndrome 5	2016-04-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781597	SCV000919768	uncertain significance	not specified	2018-04-30	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.831A>C (p.Glu277Asp) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant and a study combining data from several in silico tools and structural analyses predicts the variant to have no effect on MSH6 function (Terui_2013). The variant allele was found at a frequency of 2.5e-05 (7/276832 control chromosomes) in all ethnicities, but was found predominantly in the African subpopulation (6/24016; frequency of 0.00025). This frequency is approximately 2 fold higher than expected for a pathogenic variant in MSH6 causing Lynch Syndrome (0.00025vs 0.00014), suggesting the variant may be a benign polymorphism in the African subpopulation. To our knowledge, no occurrence of c.831A>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign until addtional information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235181	SCV001134457	uncertain significance	not provided	2023-03-06	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0002 (5/24952 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an affected individual with breast cancer (PMID: 25186627 (2015)), as well as in a cohort of individuals with features of Cowden (CS) or Bannayan-Riley-Ruvalcaba (BRRS) syndrome (PMID: 29684080 (2018)). 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.
Color Diagnostics, LLC DBA Color Health	RCV000160656	SCV001356388	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-15	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 277 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 individuals affected with breast cancer (PMID: 25186627, 29684080). This variant has been identified in 6/282520 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.
Sema4, Sema4	RCV000160656	SCV002536356	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-11	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002484996	SCV002788075	uncertain significance	Endometrial carcinoma; Lynch syndrome 5; Mismatch repair cancer syndrome 3	2022-03-31	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000411901	SCV004019015	uncertain significance	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
PreventionGenetics, part of Exact Sciences	RCV004535042	SCV004115051	uncertain significance	MSH6-related disorder	2023-08-23	criteria provided, single submitter	clinical testing	The MSH6 c.831A>C variant is predicted to result in the amino acid substitution p.Glu277Asp. This variant has been reported in an individual with breast cancer (supporting info 002, Tung et al. 2015. PubMed ID: 25186627). It has also been reported in a breast cancer specimen from The Cancer Genome Atlas (Table S9, Yehia et al. 2018. PubMed ID: 29684080). This variant is reported in 0.020% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-48025953-A-C) and is interpreted as uncertain by the vast majority of submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/182612/?new_evidence=true). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV003462093	SCV004197604	uncertain significance	Endometrial carcinoma	2023-10-19	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998490	SCV004839283	uncertain significance	Lynch syndrome	2023-09-17	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 277 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in 1 individual affected with breast cancer (PMID:25186627). This variant has been identified in 6/282520 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.