ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1386+1G>A (rs267607957)

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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) RCV000076137 SCV000107152 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Invitae RCV000684786 SCV000253799 pathogenic Hereditary nonpolyposis colon cancer 2019-11-13 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 8 of the MSH2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic. This particular variant has been reported in the literature in two individuals affected with Lynch syndrome (PMID: 15849733). Experimental studies have shown that this variant leads to exclusion of exon 8 from the MSH2 transcript (PMID: 16395668, 19669161). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000491969 SCV000580476 pathogenic Hereditary cancer-predisposing syndrome 2018-10-03 criteria provided, single submitter clinical testing Functionally-validated splicing mutation;Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000076137 SCV000592500 pathogenic Lynch syndrome 2014-08-26 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000076137 SCV000696210 pathogenic Lynch syndrome 2016-05-13 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.1386+1G>A variant involves the alteration of a conserved intronic nucleotide with 5/5 splice prediction tools calculating a significant effect on splicing, which is further supported by functional studies showing an impact on splicing. The variant of interest has not been observed in the general population and has been reported in multiple affected individuals via publications, along with multiple clinical laboratories/databases citing the variant as "likely pathogenic/pathogenic." Therefore, the variant of interest is classified as Pathogenic.

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