Submissions for variant NM_000179.3(MSH6):c.1652G>A (p.Gly551Asp)

gnomAD frequency: 0.00001  dbSNP: rs587779917

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115380	SCV000149289	uncertain significance	not provided	2015-10-27	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.1652G>A at the cDNA level, p.Gly551Asp (G551D) at the protein level, and results in the change of a Glycine to an Aspartic Acid (GGC>GAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Gly551Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glycine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Gly551Asp occurs at a position that is conserved across species and is located in domain II of the MutS domain (Terui 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH6 Gly551Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000216184	SCV000275797	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-16	criteria provided, single submitter	clinical testing	The p.G551D variant (also known as c.1652G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 1652. The glycine at codon 551 is replaced by aspartic acid, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000473749	SCV000551293	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 551 of the MSH6 protein (p.Gly551Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 127562). 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.
Counsyl	RCV000662991	SCV000785982	uncertain significance	Lynch syndrome 5	2018-01-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000216184	SCV001735070	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-28	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 551 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 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.
Myriad Genetics, Inc.	RCV000662991	SCV004019061	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000115380	SCV004221152	uncertain significance	not provided	2023-02-09	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000017 (2/114496 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in the somatic state in an individual with cutaneous squamous cell carcinoma (PMID: 25303977 (2014)). 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV003997236	SCV004841824	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 551 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 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.