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
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076088 SCV000107103 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Ambry Genetics RCV000491760 SCV000580384 pathogenic Hereditary cancer-predisposing syndrome 2018-05-22 criteria provided, single submitter clinical testing The c.1276+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 7 of the MSH2 gene. In one study, this mutation was detected in a Danish family with colorectal cancer and was found to segregate with disease within the family. Additionally, this study used a minigene assay to show that c.1276+1G>T causes aberrant splicing leading to an in-frame deletion of 16 amino acids in the MSH6/MSH3 interaction domain of the MSH2 protein (Petersen SM et al. BMC Med. Genet., 2013 Oct;14:103). This mutation has also been reported in two HNPCC families (Bisgaard ML et al. Hum. Mutat., 2002 Jul;20:20-7; Nilbert M et al. Fam. Cancer, 2009 Jun;8:75-83) and in an individual with a colorectal tumor displaying high microsatellite instability and loss of the MSH2 protein on immunohistochemical analysis (Mangold E et al. J. Pathol., 2005 Dec;207:385-95). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Invitae RCV000707663 SCV000836768 pathogenic Hereditary nonpolyposis colorectal neoplasms 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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