Submissions for variant NM_000179.3(MSH6):c.1793A>G (p.Lys598Arg)

dbSNP: rs587779919

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000759845	SCV000149293	uncertain significance	not provided	2022-12-23	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22949387, 21120944, 26976419)
Invitae	RCV000168326	SCV000219013	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 598 of the MSH6 protein (p.Lys598Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 26976419). ClinVar contains an entry for this variant (Variation ID: 127565). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MSH6 protein function with a negative predictive value of 95%. 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.
Genetic Services Laboratory, University of Chicago	RCV000115384	SCV000595858	uncertain significance	not specified	2017-03-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000565738	SCV000662354	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-27	criteria provided, single submitter	clinical testing	The p.K598R variant (also known as c.1793A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 1793. The lysine at codon 598 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported in a cohort of 488 patients with stages I to III breast cancer who were tested with a 25-gene panel test (Tung N et al. J. Clin. Oncol., 2016 May;34:1460-8). This amino acid position is well 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.
Counsyl	RCV000663315	SCV000786584	uncertain significance	Lynch syndrome 5	2018-05-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759845	SCV000889460	uncertain significance	not provided	2023-06-08	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with breast cancer (PMID: 26976419 (2016)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000565738	SCV000911465	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-29	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 598 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 at least one individual affected with breast cancer (PMID: 26976419). 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.
Myriad Genetics, Inc.	RCV000663315	SCV004019071	uncertain significance	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
All of Us Research Program, National Institutes of Health	RCV003997238	SCV004840118	uncertain significance	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 598 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 at least one individual affected with breast cancer (PMID: 26976419). 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.