Submissions for variant NM_000179.3(MSH6):c.938A>G (p.Lys313Arg)

dbSNP: rs753373644

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001019248	SCV001180580	uncertain significance	Hereditary cancer-predisposing syndrome	2018-04-06	criteria provided, single submitter	clinical testing	The p.K313R variant (also known as c.938A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 938. The lysine at codon 313 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. In addition, the CoDP in silico tool predicts this alteration to have minor impact on molecular function, with a score of 0.000 (Terui H et al. J. Biomed. Sci. 2013 Apr;20:25). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV001303030	SCV001492261	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2021-03-09	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 220584). This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with arginine at codon 313 of the MSH6 protein (p.Lys313Arg). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and arginine.
GeneDx	RCV001753618	SCV002005375	uncertain significance	not provided	2019-08-29	criteria provided, single submitter	clinical testing	Not observed 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; Has not been previously published as pathogenic or benign to our knowledge
All of Us Research Program, National Institutes of Health	RCV003997647	SCV004834242	uncertain significance	Lynch syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 313 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 not been reported in individuals affected with MSH6-related disorders in the literature. This variant has not been identified 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.