Submissions for variant NM_000179.3(MSH6):c.749T>C (p.Val250Ala)

gnomAD frequency: 0.00004  dbSNP: rs587781275

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000128926	SCV000172796	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-05	criteria provided, single submitter	clinical testing	The p.V250A variant (also known as c.749T>C), located in coding exon 4 of the MSH6 gene, results from a T to C substitution at nucleotide position 749. The valine at codon 250 is replaced by alanine, an amino acid with similar properties. This alteration has been reported in a prostate cancer and an ovarian cancer patient from a cohort of 4034 cancer cases from The Cancer Genome Atlas (Lu C et al. Nat Commun. 2015 Dec 22;6:10086). This amino acid position is highly conserved through mammals but not in all available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000656890	SCV000211262	uncertain significance	not provided	2024-04-04	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, ovarian, or prostate cancer (PMID: 26689913, 27153395); This variant is associated with the following publications: (PMID: 25980754, 27153395, 26689913, 20579941, 21437237)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168003	SCV000218654	likely benign	Hereditary nonpolyposis colorectal neoplasms	2025-02-04	criteria provided, single submitter	clinical testing
Counsyl	RCV000410809	SCV000488935	uncertain significance	Lynch syndrome 5	2016-07-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128926	SCV000685520	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-12	criteria provided, single submitter	clinical testing	This missense variant replaces valine with alanine at codon 250 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 breast and an individual affected with prostate cancer (PMID: 26689913). This variant has been identified in 8/282434 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000761137	SCV000891053	uncertain significance	Lynch syndrome	2020-10-15	criteria provided, single submitter	clinical testing	The MSH6 c.749T>C (p.Val250Ala) missense change has a maximal subpopulation frequency of 0.0062% in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/variant/2-48025871-T-C). Five 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 a prostate tumor sample bearing more confirmed somatic mutations than expected, possibly suggestive of a mutator phenotype (PMID: 20579941). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting, BP4.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000202238	SCV000917767	uncertain significance	not specified	2019-05-24	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.749T>C (p.Val250Ala) results in a non-conservative amino acid change in 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 2.8e-05 in 251134 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.749T>C has been reported in the literature in two individuals affected with Pancreatic Adenocarcinoma or Ovarian Carcinoma respectively in a study that searched for candidate germline cancer predisposition variants in the exome sequence data from 4,034 cancer patients across 12 diverse cancer types (Lu_2015). 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genetic Services Laboratory, University of Chicago	RCV000202238	SCV002072145	uncertain significance	not specified	2017-08-14	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000410809	SCV004019008	likely benign	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Baylor Genetics	RCV003467099	SCV004197637	uncertain significance	Endometrial carcinoma	2024-03-24	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656890	SCV004222055	uncertain significance	not provided	2024-04-11	criteria provided, single submitter	clinical testing	The MSH6 c.749T>C (p.Val250Ala) variant has been reported in individuals with breast cancer (PMID: 26689913 (2015), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH6)) and prostate cancer (PMID: 26689913 (2015)). This variant has also been identified in reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH6)). The frequency of this variant in the general population, 0.000062 (8/128852 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492580	SCV004239326	uncertain significance	Breast and/or ovarian cancer	2023-03-08	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000761137	SCV004836986	uncertain significance	Lynch syndrome	2024-07-20	criteria provided, single submitter	clinical testing	This missense variant replaces valine with alanine at codon 250 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 breast and an individual affected with prostate cancer (PMID: 26689913). This variant has been identified in 8/282434 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000761137	SCV005919431	uncertain significance	Lynch syndrome	2024-06-05	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000202238	SCV000257306	uncertain significance	not specified		no assertion criteria provided	clinical testing