Submissions for variant NM_000251.3(MSH2):c.2171C>T (p.Thr724Met)

gnomAD frequency: 0.00001  dbSNP: rs63751125

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160603	SCV000211199	uncertain significance	not provided	2014-05-19	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.2171C>T at the cDNA level, p.Thr724Met (T724M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Thr724Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Threonine and Methionine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Thr724Met occurs at a position that is fully conserved across species and is predicted to be located within the ATPase functional domain (Lutzen 2008). In addition, in silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH2 Thr724Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000492028	SCV000580513	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-04	criteria provided, single submitter	clinical testing	The p.T724M variant (also known as c.2171C>T), located in coding exon 13 of the MSH2 gene, results from a C to T substitution at nucleotide position 2171. The threonine at codon 724 is replaced by methionine, 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.
Invitae	RCV000629694	SCV000750650	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462091	SCV004196851	uncertain significance	Lynch syndrome 1	2023-05-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998478	SCV004832169	uncertain significance	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 724 of the MSH2 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 been reported in an individual affected with esophageal squamous cell carcinoma (PMID: 31396961). This variant has been identified in 1/251482 chromosomes 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.