Submissions for variant NM_000179.3(MSH6):c.347A>G (p.Asp116Gly)

dbSNP: rs1553410255

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000664277	SCV001181873	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-27	criteria provided, single submitter	clinical testing	The p.D116G variant (also known as c.347A>G), located in coding exon 2 of the MSH6 gene, results from an A to G substitution at nucleotide position 347. The aspartic acid at codon 116 is replaced by glycine, an amino acid with similar properties. This alteration has been identified in multiple individuals diagnosed with breast cancer (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879; Hu L et al. NPJ Breast Cancer, 2022 Apr;8:52). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000664277	SCV001734943	uncertain significance	Hereditary cancer-predisposing syndrome	2020-12-08	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 116 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 an individual affected with breast cancer (PMID: 31784482). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001861735	SCV002317033	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-03-07	criteria provided, single submitter	clinical testing	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: 549722). 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. 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. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 116 of the MSH6 protein (p.Asp116Gly).
True Health Diagnostics	RCV000664277	SCV000788050	uncertain significance	Hereditary cancer-predisposing syndrome	2017-08-11	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355964	SCV001551000	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH6 p.Asp116Gly variant was not identified in the literature nor was it identified in the dbSNP, COGR, Cosmic, MutDB, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or the Insight Hereditary Tumors database. The variant was only identified in ClinVar (1x as uncertain significance by True Health Diagnostic). The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Asp116 residue is not conserved in mammals and 3 of 4 computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.