Submissions for variant NM_000251.2(MSH2):c.2777T>A (p.Ile926Asn) (rs199747712)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000231382	SCV000284161	uncertain significance	Hereditary nonpolyposis colon cancer	2018-09-19	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with asparagine at codon 926 of the MSH2 protein (p.Ile926Asn). The isoleucine residue is moderately conserved and there is a large physicochemical difference between isoleucine and asparagine. This variant is present in population databases (rs199747712, ExAC 0.003%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 237393). 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 disruptive, 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.
GeneDx	RCV000485086	SCV000567627	uncertain significance	not provided	2016-11-21	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.2777T>A at the cDNA level, p.Ile926Asn (I926N) at the protein level, and results in the change of an Isoleucine to an Asparagine (ATC>AAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Ile926Asn was not observed at a significant allele frequency in 1000 Genomes. Since Isoleucine and Asparagine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Ile926Asn occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is located within the helix-turn-helix domain and the MSH3 and MSH6 region of interaction (Guerrette 1998, 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 Ile926Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000565937	SCV000662271	uncertain significance	Hereditary cancer-predisposing syndrome	2017-05-22	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient evidence
Color	RCV000565937	SCV000685072	uncertain significance	Hereditary cancer-predisposing syndrome	2018-10-06	criteria provided, single submitter	clinical testing
Counsyl	RCV000663160	SCV000786317	uncertain significance	Lynch syndrome I	2018-04-06	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000781561	SCV000919705	uncertain significance	not specified	2018-05-31	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.2777T>A (p.Ile926Asn) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 243906 control chromosomes. This frequency is not higher than expected for a pathogenic variant in MSH2 causing Lynch Syndrome (1.2e-05 vs 0.00057), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2777T>A in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.