ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.942+3A>G (rs193922376)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479341 SCV000565825 likely pathogenic not provided 2021-04-23 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: RNA studies demonstrate abnormal splicing (Karam 2019); Not observed in large population cohorts (Lek 2016); In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31642931, 33003368)
Invitae RCV000530947 SCV000625483 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-13 criteria provided, single submitter clinical testing This sequence change falls in intron 5 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 not been reported in the literature in individuals with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 418625). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the c.942+3 nucleotide in the MSH2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 8062247, 15222003, 19419416, 21681552, 22883484, 20682701, 10978353, 24310308, 16395668). This suggests that this nucleotide is clinically-significant, and that variants that disrupt this position are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000479341 SCV001134379 uncertain significance not provided 2018-09-12 criteria provided, single submitter clinical testing
Ambry Genetics RCV001019334 SCV001180678 likely pathogenic Hereditary cancer-predisposing syndrome 2020-05-06 criteria provided, single submitter clinical testing The c.942+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 5 in the MSH2 gene. This alteration was identified in an individual whose endometrial tumor demonstrated loss of both MSH2/MSH6 on immunohistochemistry (IHC) and had a family history of Lynch-associated cancers (Ambry internal data). While this exact alteration has not been reported in the literature, an alteration at the same nucleotide position (c.942+3A>T) has been reported in numerous individuals meeting clinical diagnostic criteria for Lynch syndrome and has been shown by multiple functional studies to cause exon 5 skipping (South CD et al. J. Natl. Cancer Inst. 2008 Feb;100(4):277-81; Desai DC et al. J. Med. Genet. 2000 Sep;37(9):646-52; Arnold S et al. Hum. Mutat. 2009 May;30(5):757-70; Auclair J et al. Hum. Mutat. 2006 Feb;27(2):145-54; Casey G et al. JAMA. 2005 Feb;293(7):799-809; Chong G et al. Hum. Mutat. 2009 Aug;30(8):E797-812). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Health, Inc RCV001019334 SCV001351193 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-09 criteria provided, single submitter clinical testing

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