ClinVar Miner

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

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000231382 SCV000284161 uncertain significance Hereditary nonpolyposis colon cancer 2019-09-09 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 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 2019-06-12 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.

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