ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2634G>A (p.Glu878=) (rs63751624)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491856 SCV000580401 pathogenic Hereditary cancer-predisposing syndrome 2018-04-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Last nucleotide of exon,Functionally-validated splicing mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes)
GeneDx RCV000519129 SCV000617594 likely pathogenic not provided 2017-08-01 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2634G>A at the cDNA level. Although the variant is silent at the codinglevel, preserving a Glutamic Acid at codon 878, it is located at the last nucleotide of exon 15 and disrupts the naturalsplice donor site leading to abnormal splicing. RT-PCR studies have demonstrated that MSH2 c.2634G>A causescomplete skipping of exon 15 (Pérez-Cabornero 2013). This variant has been observed in a family meeting Amsterdamcriteria and was found to segregate with endometrial cancer in two family members. The proband's tumor displayedabsence of the MSH2 and MSH6 proteins and microsatellite instability (MSI-H) (Pérez-Cabornero 2011). MSH2c.2634G>A was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 GenomesConsortium 2015, Lek 2016). The nucleotide which is altered, a guanine (G) at base 2634, is conserved acrossspecies. Based on currently available evidence, we consider this variant to be likely pathogenic
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076523 SCV000107553 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Variant causes splicing aberration leading to truncated protein: full inactivation of variant allele
Invitae RCV000791439 SCV000260754 pathogenic Hereditary nonpolyposis colon cancer 2018-12-18 criteria provided, single submitter clinical testing This sequence change affects codon 878 of the MSH2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MSH2 protein. This variant also falls at the last nucleotide of exon 15 of the MSH2 coding sequence, which is part of the consensus splice site for this exon. 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 (LS) (PMID: 21778331, 23523604, Invitae), and shown to segregate with LS-associated cancers in several families (PMID: 21778331, Invitae). ClinVar contains an entry for this variant (Variation ID: 91021). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this silent change causes the out-of-frame skipping of exon 15 (PMID: 23523604). For these reasons, this variant has been classified as Pathogenic.

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