Submissions for variant NM_000179.3(MSH6):c.984C>G (p.Ser328Arg)

dbSNP: rs138143769

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130197	SCV000185034	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-02	criteria provided, single submitter	clinical testing	The p.S328R variant (also known as c.984C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 984. The serine at codon 328 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000679242	SCV000566940	uncertain significance	not provided	2024-12-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 21437237)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000630133	SCV000751089	likely benign	Hereditary nonpolyposis colorectal neoplasms	2025-01-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679242	SCV000805911	uncertain significance	not provided	2017-10-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130197	SCV000908363	uncertain significance	Hereditary cancer-predisposing syndrome	2019-09-10	criteria provided, single submitter	clinical testing	This missense variant replaces serine with arginine at codon 328 of the MSH6 protein. Computational prediction tool 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251378 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	RCV000679242	SCV001134463	uncertain significance	not provided	2021-01-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460915	SCV004195670	uncertain significance	Endometrial carcinoma	2024-01-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004806077	SCV005429243	uncertain significance	Lynch syndrome	2024-02-22	criteria provided, single submitter	clinical testing	This missense variant replaces serine with arginine at codon 328 of the MSH6 protein. Computational prediction tool 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251378 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.