Submissions for variant NM_000179.3(MSH6):c.3215G>A (p.Gly1072Asp)

dbSNP: rs781243845

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215059	SCV000278516	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-15	criteria provided, single submitter	clinical testing	The p.G1072D variant (also known as c.3215G>A), located in coding exon 5 of the MSH6 gene, results from a G to A substitution at nucleotide position 3215. The glycine at codon 1072 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been identified in 1/302 pancreatic cancer patients with positive family histories (Chaffee KG et al. Genet. Med., 2018 01;20:119-127). 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.
Color Diagnostics, LLC DBA Color Health	RCV000215059	SCV000685369	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-21	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 1072 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a cohort of individuals affected with pancreatic cancer who had a family history of the disease (PMID: 28726808). 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.
Invitae	RCV000814199	SCV000954600	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-28	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 1072 of the MSH6 protein (p.Gly1072Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 234031). 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.
Illumina Laboratory Services, Illumina	RCV001142304	SCV001302731	uncertain significance	Lynch syndrome 5	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267969	SCV002552326	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003469094	SCV004195577	uncertain significance	Endometrial carcinoma	2023-08-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998595	SCV004834984	uncertain significance	Lynch syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 1072 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a cohort of individuals affected with pancreatic cancer who had a family history of the disease (PMID: 28726808). 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.