ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2503A>C (p.Asn835His) (rs41295296)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656882 SCV000149428 uncertain significance not provided 2019-01-17 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2503A>C at the cDNA level, p.Asn835His (N835H) at the protein level, and results in the change of an Asparagine to a Histidine (AAT>CAT). MSH2 Asn835His has been reported in individuals with ovarian cancer, breast cancer, endometrial cancer, and colon cancer (Hampel 2006, Barnetson 2008, South 2009, Maxwell 2015). Barnetson et al. (2008) classified this variant as benign based on its presence in one healthy control, lack of microsatellite instability in the colon tumor of one patient, as well as conservation and in silico predictions. This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH2 Asn835His is located within the ATPase domain (Lutzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH2 Asn835His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115519 SCV000183751 likely benign Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification;Structural Evidence
Invitae RCV000656882 SCV000254409 likely benign not provided 2019-03-04 criteria provided, single submitter clinical testing
Counsyl RCV000410916 SCV000487953 uncertain significance Lynch syndrome I 2015-12-06 criteria provided, single submitter clinical testing
Color RCV000115519 SCV000537528 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-07 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212621 SCV000601468 uncertain significance not specified 2017-04-03 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000212621 SCV000712835 uncertain significance not specified 2016-12-28 criteria provided, single submitter clinical testing The p.Asn835His variant in MSH2 has been reported in 2 individuals with Lynch sy ndrome-associated cancers (Hampel 2006, Barnetson 2008), where a lack of microsa tellite instability was observed in one of the individuals' colon tumor. This va riant has also been identified in 1/66684 of European chromosomes by the Exome A ggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs41295296). Computational prediction tools and conservation analysis do not provide strong s upport for or against an impact to the protein. Furthermore, this variant was cl assified as a variant of uncertain significance on Sept. 5, 2013 by the ClinGen- approved InSiGHT expert panel (ClinVar SCV000107519.2). In summary, the clinical significance of the p.Asn835His variant is uncertain.

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