ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1276+1G>T (rs267607950)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491760 SCV000580384 pathogenic Hereditary cancer-predisposing syndrome 2013-05-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other acmg-defined mutation (i.e. initiation codon or gross deletion)
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076088 SCV000107103 likely pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Interrtups canonical donor splice site
Invitae RCV000707663 SCV000836768 pathogenic Hereditary nonpolyposis colon cancer 2018-06-28 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 7 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 several individuals and families affected with Lynch syndrome (PMID: 12112654, 18566915, 24090359, 16216036) and reported to segregate with the disease in at least one of the affected families (PMID: 24090359). ClinVar contains an entry for this variant (Variation ID: 90592). Experimental studies have shown that this splice donor change causes the activation of a cryptic splice site in exon 7 resulting in the in-frame deletion of 16 amino acids in vitro (PMID: 24090359). Deletion of this region is expected to disrupt the MSH3/MSH6 interaction domain, which is required for proper MSH2 protein function (PMID: 18822302, 9774676). A different variant affecting this nucleotide (c.1276+1G>A) has been determined to be pathogenic (PMID: 15849733, 19669161). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. 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). For these reasons, this variant has been classified as Pathogenic.

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