ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2459-12A>G (rs267608012)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160620 SCV000211218 uncertain significance not provided 2014-09-22 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2459-12A>G or IVS14-12A>G and consists of an A>G nucleotide substitution at the -12 position of intron 14 of the MSH2 gene. Multiple in silico models predict this variant to damage the nearby natural acceptor site, and to possibly cause abnormal gene splicing. This variant was observed in an individual with either a personal or family history suggestive of Lynch syndrome (Mangold 2005). MSH2 c.2459-12A>G was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Based on currently available information, it is unclear whether MSH2 c.2459-12A>G is pathogenic or benign. We consider it to be a variant of uncertain significance.
Mendelics RCV000076479 SCV000837853 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000076479 SCV000887427 likely pathogenic Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MSH2 NM_000251.2:c.2459-12A>G has a 98.8% probability of pathogenicity based on combining prior probability from public data with likelihood ratios of 1.56, 1.56, 1.56, 1.56, and 26.5 to 1, generated from evidence of seeing this as a somatic mutation in 5 independent tumors 4 of which did not have loss of heterozygosit and one of which had loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214.

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