ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1077-2A>C (rs267607943)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076023 SCV000107043 pathogenic Lynch syndrome I 2014-10-10 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics RCV000491115 SCV000580511 pathogenic Hereditary cancer-predisposing syndrome 2019-06-12 criteria provided, single submitter clinical testing Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes);RNA Studies
Color RCV000491115 SCV001341055 pathogenic Hereditary cancer-predisposing syndrome 2019-05-13 criteria provided, single submitter clinical testing
Invitae RCV001207225 SCV001378569 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-10-02 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 6 of the MSH2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with Lynch syndrome (PMID: 24278394, 14970868). This variant is also known as IVS6-2A>C in the literature. ClinVar contains an entry for this variant (Variation ID: 90528). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). 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.

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