Submissions for variant NM_000251.3(MSH2):c.134C>A (p.Ala45Glu)

dbSNP: rs63750285

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001238108	SCV001410905	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2019-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with glutamic acid at codon 45 of the MSH2 protein (p.Ala45Glu). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Molecular Oncology - Human Genetics Lab, University of Sao Paulo	RCV001843573	SCV002103149	likely pathogenic	Hepatoblastoma		no assertion criteria provided	research