Submissions for variant NM_000251.3(MSH2):c.47A>C (p.Glu16Ala)

dbSNP: rs745771647

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484013	SCV000570223	uncertain significance	not provided	2017-03-24	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.47A>C at the cDNA level, p.Glu16Ala (E16A) at the protein level, and results in the change of a Glutamic Acid to an Alanine (GAG>GCG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Glu16Ala was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamic Acid and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Glu16Ala occurs at a position that is conserved across species and is located within the mismatch binding domain (Lützen 2008, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Glu16Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000540608	SCV000625430	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 16 of the MSH2 protein (p.Glu16Ala). 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: 421121). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 80%. 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.
Ambry Genetics	RCV002329151	SCV002634464	likely benign	Hereditary cancer-predisposing syndrome	2021-11-04	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.
Baylor Genetics	RCV003464016	SCV004196216	uncertain significance	Lynch syndrome 1	2023-10-04	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000484013	SCV004224900	uncertain significance	not provided	2022-04-14	criteria provided, single submitter	clinical testing	PP3, PM2
All of Us Research Program, National Institutes of Health	RCV004003345	SCV004833633	uncertain significance	Lynch syndrome	2023-04-28	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with alanine at codon 16 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 not been reported in individuals affected with MSH2-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.