ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2634+5G>C (rs267608017)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076521 SCV000107551 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Variant causes splicing aberration, 2 MSI-H tumours, co-segregation with disease & MAF 0.00
Ambry Genetics RCV000491990 SCV000580393 pathogenic Hereditary cancer-predisposing syndrome 2019-03-04 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s);Other strong data supporting pathogenic classification
Integrated Genetics/Laboratory Corporation of America RCV000076521 SCV000696254 pathogenic Lynch syndrome 2019-09-05 criteria provided, single submitter clinical testing Variant summary: MSH2 c.2634+5G>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site, while one predicts the variant weakens a 5' donor site. Publications reported experimental evidence confirming that this variant disrupts the splice-donor site, resulting in exon 15 skipping, and a frame-shift at the protein level (Davoodi-Semiromi_2000, Barnetson_2008). The variant was absent in 253506 control chromosomes (gnomAD and publications). c.2634+5G>C has been reported in the literature in multiple individuals affected with Lynch Syndrome, including at least one family where the variant co-segregated with the disease; microsatellite instability with loss of the MSH2/MSH6 proteins in the associated tumor was also noted (e.g. Davoodi-Semiromi_2000, Casey_2005, Barnetson_2008, Thompson_2013, Mork_2019). These data indicate that the variant is very likely to be associated with disease. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color RCV000491990 SCV000905444 pathogenic Hereditary cancer-predisposing syndrome 2018-01-26 criteria provided, single submitter clinical testing
Invitae RCV001063481 SCV001228328 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-09-12 criteria provided, single submitter clinical testing This sequence change falls in intron 15 of the MSH2 gene. It does not directly change the encoded amino acid sequence of the MSH2 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with Lynch syndrome-related cancers in families (PMID: 18033691, 11074494). ClinVar contains an entry for this variant (Variation ID: 91019). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 15713769, 18033691). For these reasons, this variant has been classified as Pathogenic.

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