Submissions for variant NM_000179.3(MSH6):c.334A>G (p.Asn112Asp)

dbSNP: rs864622397

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204549	SCV000260470	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 112 of the MSH6 protein (p.Asn112Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 220150). 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.
Ambry Genetics	RCV000491364	SCV000580297	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-07	criteria provided, single submitter	clinical testing	The p.N112D variant (also known as c.334A>G), located in coding exon 2 of the MSH6 gene, results from an A to G substitution at nucleotide position 334. The asparagine at codon 112 is replaced by aspartic acid, an amino acid with highly similar properties. 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000491364	SCV000690346	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-06	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with aspartic acid at codon 112 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 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.
Mendelics	RCV003491957	SCV001135780	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
GeneDx	RCV001753613	SCV002005715	uncertain significance	not provided	2019-10-15	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003493500	SCV004243577	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Molecular Oncology - Human Genetics Lab, University of Sao Paulo	RCV001843493	SCV002103117	uncertain significance	Hepatoblastoma		no assertion criteria provided	research