ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2635-2A>G (rs1114167818)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000680205 SCV000807669 likely pathogenic Lynch syndrome I 2018-06-13 reviewed by expert panel curation Variant at IVS±2
Invitae RCV001042011 SCV001205669 likely pathogenic Hereditary nonpolyposis colon cancer 2019-12-24 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in the last intron (intron 15) of the MSH2 gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with Lynch syndrome in a family (PMID: 29690800). Also, the disruption of this splice site has been observed in several individuals with clinical features of Lynch syndrome (PMID: 21286823, 27601186, 15849733, 12624141, Invitae). ClinVar contains an entry for this variant (Variation ID: 561173). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. 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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