Submissions for variant NM_000179.3(MSH6):c.1069G>A (p.Asp357Asn)

dbSNP: rs771529531

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485837	SCV000570086	uncertain significance	not provided	2018-12-20	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.1069G>A at the cDNA level, p.Asp357Asn (D357N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAT>AAT). This variant has been observed in at least one individual with a history of ovarian cancer (Loizidou 2014). MSH6 Asp357Asn was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Aspartic Acid and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH6 Asp357Asn is located within the nuclear localization signals (Gassman 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Asp357Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000582356	SCV000690170	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-12	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 357 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 ovarian cancer (PMID: 25133505). This variant has been identified in 1/251178 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.
Invitae	RCV000629703	SCV000750659	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000485837	SCV001134387	uncertain significance	not provided	2018-10-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000582356	SCV001178226	likely benign	Hereditary cancer-predisposing syndrome	2022-12-15	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.
Baylor Genetics	RCV003464014	SCV004195532	uncertain significance	Endometrial carcinoma	2023-09-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004003341	SCV004837625	uncertain significance	Lynch syndrome	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 357 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with ovarian cancer (PMID: 25133505). This variant has been identified in 1/251178 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.