ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2320A>G (p.Ile774Val) (rs775464903)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000468999 SCV000548163 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-11-25 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 774 of the MSH2 protein (p.Ile774Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 28765196, Invitae, external communication). ClinVar contains an entry for this variant (Variation ID: 408475). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000492021 SCV000580556 likely pathogenic Hereditary cancer-predisposing syndrome 2019-08-02 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes)

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