Submissions for variant NM_000179.3(MSH6):c.1406A>G (p.Tyr469Cys)

dbSNP: rs748165218

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213108	SCV000275158	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-12	criteria provided, single submitter	clinical testing	The p.Y469C variant (also known as c.1406A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 1406. The tyrosine at codon 469 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was identified in a Japanese population cohort of 2049 individuals who underwent whole-genome sequencing (Yamaguchi-Kabata Y et al. J Hum Genet, 2018 Feb;63:213-230). This alteration was also observed in a cohort of 431 patients with wild-type PTEN who met at least the relaxed diagnostic criteria of the International Cowden Consortium (Lee YR et al. N Engl J Med, 2020 05;382:2103-2116). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000226561	SCV000283713	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 469 of the MSH6 protein (p.Tyr469Cys). This variant is present in population databases (rs748165218, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 231340). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MSH6 protein function. 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.
GeneDx	RCV000485048	SCV000569035	uncertain significance	not provided	2023-09-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33007869, 17531815, 21120944, 29192238, 35264596, 36243179, 32980694, 32459922)
Color Diagnostics, LLC DBA Color Health	RCV000213108	SCV000690200	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-23	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 469 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 33007869), however, this individual also had a pathogenic TP53 variant that likely accounts for the disease. In a pancreatic cancer case-control study, this variant was observed in one affected individual and two unaffected controls (PMID: 32980694). This variant has been identified in 3/251178 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in healthy control individuals (PMID: 32980694). 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.
Mendelics	RCV000708866	SCV000837881	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000485048	SCV000888237	uncertain significance	not provided	2023-08-01	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMIDs: 35264596 (2022), 33007869 (2020)), lung cancer (PMID: 35712480 (2022)), and in healthy controls (PMID: 36243179 (2022)). In a breast cancer association study, this variant was observed in 3 breast cancer cases and in 1 control individual (see LOVD (http://databases.lovd.nl/shared/genes/MSH6) and PMID: 33471991 (2021)). The frequency of this variant in the general population, 0.000012 (3/251178 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 conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
GenomeConnect - Invitae Patient Insights Network	RCV000485048	SCV001749338	not provided	not provided		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 08-22-2015 by Ambry Genetics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.