Submissions for variant NM_000179.3(MSH6):c.1403G>A (p.Arg468His)

gnomAD frequency: 0.00001  dbSNP: rs41295268

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074654	SCV000107856	likely benign	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability 0.001-0.049
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524110	SCV000551260	likely benign	Hereditary nonpolyposis colorectal neoplasms	2025-02-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000564062	SCV000662362	likely benign	Hereditary cancer-predisposing syndrome	2020-03-27	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	RCV000564062	SCV000685190	uncertain significance	Hereditary cancer-predisposing syndrome	2024-07-26	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 468 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant to have mismatch repair activity similar to wild type (PMID: 31965077). This variant has been reported in at least four individuals affected with colorectal cancer (PMID: 18033691, 18809606, 34172528) and in one individual affected with Lynch syndrome (PMID: 17854147). Two of these individuals, however, exhibited clinical features inconsistent with MSH6-associated cancer such as microsatellite stability and normal MSH6 immuno-histochemistry results (PMID: 18033691, 18809606). This variant has been identified in 8/251140 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	RCV000588584	SCV000695782	likely benign	not specified	2021-05-24	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1403G>A (p.Arg468His) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 253156 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1403G>A has been reported in the literature in individuals affected with colorectal cancer (example, Hampel_2008, Houlleberghs_2017). At-least one of these reported a microsatellite stable (MSS) and MLH1+/MSH2+MSH6+ IHC profile (Barneston_2008). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on MMR (mismatch repair) protein function (Houlleberghs_2017). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=2; benign, n=1; VUS, n=1). At-least one submitter report a likely benign outcome reports a non-specified co-occurrence with mutation in same gene (phase unknown) supporting their classification and cites overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics	RCV000986714	SCV001135804	benign	Lynch syndrome 5	2019-05-28	criteria provided, single submitter	clinical testing
GeneDx	RCV001582559	SCV001819075	uncertain significance	not provided	2024-01-26	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate MMR proficiency in a site-directed mutagenesis assay (PMID: 28531214); This variant is associated with the following publications: (PMID: 25637381, 19389263, 17854147, 18033691, 18809606, 23621914, 21153778, 28922847, 30798936, 32926152, 34426522, 2563738, 18067074, 35980532, 17531815, 21120944, 28531214, 36243179, 34326862)
All of Us Research Program, National Institutes of Health	RCV000074654	SCV004841350	uncertain significance	Lynch syndrome	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 468 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An in vitro DNA mismatch repair assay reported this variant to have wildtype repair activity (PMID: 31965077) while a selection screen for pathogenic MSH6 variants failed to detect this variant (PMID: 28531214). This variant has been reported in at least four individuals affected with colorectal cancer (PMID: 18033691, 18809606, 34172528) and in one individual affected with Lynch syndrome (PMID: 17854147). Two of these individuals, however, exhibited clinical features inconsistent with MSH6-associated cancer such as microsatellite stability and normal MSH6 immuno-histochemistry results (PMID: 18033691, 18809606). This variant has been identified in 8/251140 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001582559	SCV005877669	likely benign	not provided	2024-09-26	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000074654	SCV005917020	likely benign	Lynch syndrome	2024-12-31	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148649	SCV000190364	uncertain significance	Colorectal cancer, non-polyposis	2014-06-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004537272	SCV004740179	likely benign	MSH6-related disorder	2023-02-03	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).