Submissions for variant NM_000179.3(MSH6):c.521G>A (p.Arg174Lys)

gnomAD frequency: 0.00001  dbSNP: rs863224629

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409062	SCV000489194	uncertain significance	Lynch syndrome 5	2016-08-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000491997	SCV000580347	uncertain significance	Hereditary cancer-predisposing syndrome	2024-07-25	criteria provided, single submitter	clinical testing	The p.R174K variant (also known as c.521G>A), located in coding exon 3 of the MSH6 gene, results from a G to A substitution at nucleotide position 521. The arginine at codon 174 is replaced by lysine, an amino acid with highly similar properties. 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.
Color Diagnostics, LLC DBA Color Health	RCV000491997	SCV000905483	uncertain significance	Hereditary cancer-predisposing syndrome	2019-07-26	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with lysine at codon 174 of the MSH6 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001337371	SCV001530973	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-11-15	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. 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. ClinVar contains an entry for this variant (Variation ID: 216319). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 174 of the MSH6 protein (p.Arg174Lys).
Myriad Genetics, Inc.	RCV000409062	SCV004018945	uncertain significance	Lynch syndrome 5	2023-03-28	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004998406	SCV005623517	uncertain significance	not provided	2024-07-30	criteria provided, single submitter	clinical testing	The MSH6 c.521G>A (p.Arg174Lys) variant has not been reported in individuals with MSH6-related conditions in the published literature. The frequency of this variant in the general population, 0.000013 (2/152146 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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.