Submissions for variant NM_000179.3(MSH6):c.2950A>G (p.Asn984Asp)

dbSNP: rs146359682

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483801	SCV000566324	uncertain significance	not provided	2018-08-24	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.2950A>G at the cDNA level, p.Asn984Asp (N984D) at the protein level, and results in the change of an Asparagine to an Aspartic Acid (AAT>GAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Asn984Asp was not observed in large population cohorts (Lek 2016). Since Asparagine and Aspartic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. MSH6 Asn984Asp is located in the clamp domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether MSH6 Asn984Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae	RCV000546084	SCV000624804	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-30	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 984 of the MSH6 protein (p.Asn984Asp). 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: 418917). 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	RCV000574429	SCV000669903	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-23	criteria provided, single submitter	clinical testing	The p.N984D variant (also known as c.2950A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 2950. The asparagine at codon 984 is replaced by aspartic acid, an amino acid with highly similar properties. This variant was reported in 2/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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	RCV000574429	SCV001343126	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-21	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with aspartic acid at codon 984 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. In a large breast cancer case-control study, this variant was observed in 2/60466 cases and 0/53461 unaffected controls (PMID: 33471991). 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.
Baylor Genetics	RCV003463985	SCV004197596	uncertain significance	Endometrial carcinoma	2023-10-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004002276	SCV004839045	uncertain significance	Lynch syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with aspartic acid at codon 984 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. In a large breast cancer case-control study, this variant was observed in 2/60466 cases and 0/53461 unaffected controls (PMID: 33471991). 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.