Submissions for variant NM_000251.3(MSH2):c.332C>T (p.Ala111Val)

dbSNP: rs1672561306

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001229939	SCV001402402	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-08-22	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: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 111 of the MSH2 protein (p.Ala111Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of MSH2-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 957030).
GeneDx	RCV001760227	SCV001998073	uncertain significance	not provided	2019-10-08	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); While protein-based in silico analysis supports that this variant does not alter protein structure/function, splice predictors support a deleterious effect. However, in the absence of RNA or functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002322108	SCV002606581	likely benign	Hereditary cancer-predisposing syndrome	2023-11-16	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355866	SCV001550875	uncertain significance	Lynch syndrome		no assertion criteria provided	clinical testing	The MSH2 p.Ala111Val variant was not identified in the literature nor in the following databases: dbSNP, ClinVar, Clinvitae, COGR, Cosmic, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016). The p.Ala111 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.