Submissions for variant NM_000179.3(MSH6):c.2183A>G (p.Lys728Arg)

dbSNP: rs35552856

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000564228	SCV000662388	likely benign	Hereditary cancer-predisposing syndrome	2022-10-13	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.
Invitae	RCV000688061	SCV000815658	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765685	SCV000897027	uncertain significance	Endometrial carcinoma; Mismatch repair cancer syndrome 1; Lynch syndrome 5	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000564228	SCV000908394	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-17	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 728 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 rectal cancer (PMID: 25559809). This variant has been identified in 3/250944 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.
GeneDx	RCV001591322	SCV001814822	uncertain significance	not provided	2019-10-28	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with colorectal cancer (Chubb 2015); This variant is associated with the following publications: (PMID: 25559809)
Sema4, Sema4	RCV000564228	SCV002535707	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-04	criteria provided, single submitter	curation
Baylor Genetics	RCV003470823	SCV004195773	uncertain significance	Endometrial carcinoma	2023-05-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004000868	SCV004836152	uncertain significance	Lynch syndrome	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 728 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 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 3/250944 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.