Submissions for variant NM_000179.3(MSH6):c.1144C>T (p.His382Tyr)

gnomAD frequency: 0.00004  dbSNP: rs587779207

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162700	SCV000213155	likely benign	Hereditary cancer-predisposing syndrome	2018-11-16	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.
GeneDx	RCV000213163	SCV000279483	uncertain significance	not provided	2024-11-26	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26333163, 31422574, 32068069, 33471991, 17531815, 21120944, 26689913)
Counsyl	RCV000411429	SCV000489167	uncertain significance	Lynch syndrome 5	2016-08-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000627690	SCV000551091	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-12-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162700	SCV000690175	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-02	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 382 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 and/or ovarian cancer (PMID: 26689913, 32068069) and in an individual affected with colorectal cancer (LOVD database; https://databases.lovd.nl/shared/individuals/00187081). This variant has been identified in 6/282326 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001255541	SCV001432008	uncertain significance	not specified	2021-05-19	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1144C>T (p.His382Tyr) 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 on protein function. The variant allele was found at a frequency of 1.2e-05 in 250932 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1144C>T has been reported in the literature in an individual affected with breast cancer (Lu_2015), however it was also found in an individual in a non-cancer related cohort (Kraemer_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Four labs classified the variant as VUS whle one classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000162700	SCV002535601	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-21	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000411429	SCV004019094	uncertain significance	Lynch syndrome 5	2023-03-30	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.
Baylor Genetics	RCV003460658	SCV004197666	uncertain significance	Endometrial carcinoma	2023-10-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997063	SCV004843002	uncertain significance	Lynch syndrome	2023-10-30	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 382 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 and/or ovarian cancer (PMID: 26689913, 32068069), and an individual in a cohort that was not selected for cancer phenotype (PMID: 31422574). This variant also has been reported in an individual affected with colorectal cancer (LOVD database; https://databases.lovd.nl/shared/individuals/00187081). This variant has been identified in 6/282326 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	RCV000213163	SCV005625618	uncertain significance	not provided	2024-03-21	criteria provided, single submitter	clinical testing	The MSH6 c.1144C>T (p.His382Tyr) variant has been reported in individuals with breast cancer (PMIDs: 32068069 (2020), 26689913 (2015)) as well as in reportedly healthy individuals (PMID: 31422574 (2019)). This variant has also been reported in individuals with breast cancer as well as in reportedly healthy individuals in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH6)). The frequency of this variant in the general population, 0.000039 (5/128694 chromosomes, http://gnomad.broadinstitute.org), is uninformative in 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.