ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2634+1G>A (rs267608019)

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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) RCV000076518 SCV000107548 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Ambry Genetics RCV000491073 SCV000580451 pathogenic Hereditary cancer-predisposing syndrome 2019-02-06 criteria provided, single submitter clinical testing The c.2634+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 15 of the MSH2 gene. This pathogenic splice mutation has been reported in multiple HNPCC families (Bonadona V et al. JAMA 2011 Jun;305:2304-10; Kurzawski G et al. Clin. Genet. 2006 Jan;69:40-7). This alteration was detected in an HNPCC family that met Amsterdam criteria, and further in vitro analyses indicated that this substitution resulted in a deletion of exon 15 in the transcript and consequent truncated protein (Liu B et al. Cancer Res. 1994 Sep;54:4590-4). 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 pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000506677 SCV000604260 pathogenic not specified 2016-10-06 criteria provided, single submitter clinical testing
Invitae RCV000688047 SCV000815644 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-01-02 criteria provided, single submitter clinical testing This sequence change affects a donor 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 reported in several individuals affected with Lynch syndrome (PMID: 8062247, 21642682, 25980754, 16451135). ClinVar contains an entry for this variant (Variation ID: 91016). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies demonstrated that this intronic change results in exon 15 skipping (PMID: 8062247). A different variant affecting this nucleotide (c.2634+1G>T) has been determined to be pathogenic (PMID: 12386821, 20587412). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000076518 SCV000919702 pathogenic Lynch syndrome 2018-05-16 criteria provided, single submitter clinical testing Variant summary: MSH2 c.2634+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. One publication reports experimental evidence showing exon 15 deletion associated with this variant (Liu_1994). The variant was absent in 121394 control chromosomes (ExAC). The variant, c.2634+1G>A, has been reported in the literature in several individuals affected with Lynch Syndrome (Bonadona_2011, Dymerska_2010, Liu_1994, Yurgelun_2015). These data indicate that the variant is likely associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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