Submissions for variant NM_000179.3(MSH6):c.2225A>C (p.Asn742Thr)

dbSNP: rs878853715

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000573144	SCV000673958	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-11	criteria provided, single submitter	clinical testing	The p.N742T variant (also known as c.2225A>C), located in coding exon 4 of the MSH6 gene, results from an A to C substitution at nucleotide position 2225. The asparagine at codon 742 is replaced by threonine, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001340825	SCV001534654	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2020-12-13	criteria provided, single submitter	clinical testing	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. 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 expected to disrupt MSH6 protein function. This variant has not been reported in the literature in individuals with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 237154). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with threonine at codon 742 of the MSH6 protein (p.Asn742Thr). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and threonine.
All of Us Research Program, National Institutes of Health	RCV003998716	SCV004839019	uncertain significance	Lynch syndrome	2024-08-06	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with threonine at codon 742 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.