Submissions for variant NM_000251.3(MSH2):c.619G>T (p.Ala207Ser)

dbSNP: rs63750913

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000575601	SCV000662290	uncertain significance	Hereditary cancer-predisposing syndrome	2019-10-04	criteria provided, single submitter	clinical testing	The p.A207S variant (also known as c.619G>T), located in coding exon 3 of the MSH2 gene, results from a G to T substitution at nucleotide position 619. The alanine at codon 207 is replaced by serine, an amino acid with similar properties. This alteration has been reported in the literature in a patient diagnosed with an MSI-high diffuse-type advanced gastric cancer at age 40 (Wu MS et al. Cancer Lett. 1997 Jan; 112(2):161-6). This amino acid position is poorly 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.
Invitae	RCV001858105	SCV002272723	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2021-02-28	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 not expected to disrupt MSH2 protein function. This variant has been reported in individual(s) in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 479819). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with serine at codon 207 of the MSH2 protein (p.Ala207Ser). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and serine.
All of Us Research Program, National Institutes of Health	RCV004000857	SCV004830839	uncertain significance	Lynch syndrome	2023-02-24	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 207 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (PMID: 33357406). This variant has been identified as a somatic variant in an individual affected with diffuse type advanced gastric adenocarcinoma that exhibited microsatellite instability (PMID: 9066723). 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.
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000723272	SCV000854657	uncertain significance	MSH2-related disorder	2018-04-27	no assertion criteria provided	clinical testing