Submissions for variant NM_000179.3(MSH6):c.430A>G (p.Ser144Gly)

dbSNP: rs1668701906

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001179689	SCV001344399	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-28	criteria provided, single submitter	clinical testing	This missense variant replaces serine with glycine at codon 144 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.
Ambry Genetics	RCV001179689	SCV004057504	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-29	criteria provided, single submitter	clinical testing	The p.S144G variant (also known as c.430A>G), located in coding exon 2 of the MSH6 gene, results from an A to G substitution at nucleotide position 430. The serine at codon 144 is replaced by glycine, an amino acid with similar properties. This amino acid position is conserved. 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.
Baylor Genetics	RCV003462651	SCV004197600	uncertain significance	Endometrial carcinoma	2023-10-21	criteria provided, single submitter	clinical testing
Invitae	RCV003759008	SCV004529386	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 144 of the MSH6 protein (p.Ser144Gly). 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: 920743). 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.
All of Us Research Program, National Institutes of Health	RCV004006595	SCV004829209	uncertain significance	Lynch syndrome	2023-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces serine with glycine at codon 144 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.