Submissions for variant NM_000251.3(MSH2):c.2272G>T (p.Asp758Tyr)

dbSNP: rs876658254

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215978	SCV000273258	uncertain significance	Hereditary cancer-predisposing syndrome	2015-01-07	criteria provided, single submitter	clinical testing	The p.D758Y variant (also known as c.2272G>T), located in coding exon 14 of the MSH2 gene, results from a G to T substitution at nucleotide position 2272. The aspartic acid at codon 758 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 42000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao E et al. Hum Mutat. 2008 Jun;29(6):852-60). Since supporting evidence is limited at this time, the clinical significance of p.D758Y remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000215978	SCV001351150	uncertain significance	Hereditary cancer-predisposing syndrome	2019-09-06	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with tyrosine at codon 758 of the MSH2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001222233	SCV001394327	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 758 of the MSH2 protein (p.Asp758Tyr). 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: 229891). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is expected to disrupt MSH2 function with a positive 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.
Myriad Genetics, Inc.	RCV003454615	SCV004186628	likely pathogenic	Lynch syndrome 1	2023-08-08	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 33357406]. This variant is expected to disrupt protein structure [Myriad internal data].