Submissions for variant NM_000179.3(MSH6):c.2600T>G (p.Val867Gly)

gnomAD frequency: 0.00001  dbSNP: rs139598980

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130173	SCV000185010	likely benign	Hereditary cancer-predisposing syndrome	2020-09-01	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.
GeneDx	RCV000222583	SCV000279104	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 a personal history of rectal cancer (de Rosa et al., 2016); This variant is associated with the following publications: (PMID: 23621914, 17531815, 21120944, 31391288, 27432916)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000238642	SCV000296880	uncertain significance	Lynch syndrome	2015-11-19	criteria provided, single submitter	clinical testing
Invitae	RCV000524147	SCV000551103	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130173	SCV000685301	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-18	criteria provided, single submitter	clinical testing	This missense variant replaces valine with glycine at codon 867 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with rectal cancer (PMID: 27432916). This variant has been identified in 9/281252 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	RCV000222583	SCV002046483	uncertain significance	not provided	2023-04-17	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000082 (2/24294 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with colorectal cancer (PMID: 27432916 (2016)). A published MSH6-specific algorithm suggested that this variant has no impact on the protein (PMID: 23621914 (2013)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH6)). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317097	SCV004020493	uncertain significance	not specified	2023-06-27	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2600T>G (p.Val867Gly) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) 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 3.2e-05 in 249856 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2600T>G has been reported in the literature in an individual affected with MMR-deficient rectal cancer (de Rosa_2016) and in an individual from a cohort of patients with primarily Lynch Syndrome-associated cancers whose tumor was microsatellite instable, but the variant was predicted as likely benign by the multifactorial predictive model presented in the publication (Li_2020). These reports 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. The following publications have been ascertained in the context of this evaluation (PMID: 31391288, 27432916). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments, classifiying the variant as either VUS (n=4) or benign (n=1)/likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV000238642	SCV004842759	uncertain significance	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces valine with glycine at codon 867 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with early onset, mismatch repair deficient rectal cancer (PMID: 27432916) as well as in an individual affected with an unspecified cancer (PMID: 31391288). In a large breast cancer case-control study, this variant has been reported in 5/60466 cases and 2/53461 unaffected controls (PMID: 33471991). This variant has been identified in 9/281252 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.