Submissions for variant NM_000251.3(MSH2):c.1837A>T (p.Asn613Tyr)

dbSNP: rs200147804

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235277	SCV000294074	uncertain significance	not provided	2016-03-11	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.1837A>T at the cDNA level, p.Asn613Tyr (N613Y) at the protein level, and results in the change of an Asparagine to a Tyrosine (AAT>TAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Asn613Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Asparagine and Tyrosine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Asn613Tyr occurs at a position that is not conserved and is located in Lever domain and the region of interaction with MSH6, MSH3, and EXO1 (Lützen 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Asn613Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV002411071	SCV002716987	likely benign	Hereditary cancer-predisposing syndrome	2022-10-12	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003758739	SCV004432273	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-03-08	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 performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 333574060) indicates that this missense variant is not expected to disrupt MSH2 function. This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 613 of the MSH2 protein (p.Asn613Tyr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 246493).