ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.2503A>C (p.Asn835His) (rs41295296)

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Total submissions: 9
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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 RCV001082618 SCV000254409 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-11-15 criteria provided, single submitter clinical testing
Counsyl RCV000410916 SCV000487953 uncertain significance Lynch syndrome I 2015-12-06 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115519 SCV000537528 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-26 criteria provided, single submitter clinical testing This missense variant replaces asparagine with histidine at codon 835 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with colorectal cancer, with the tumor showing low microsatellite instability and normal expression of MLH1, MSH2 and MSH6 protein (PMID: 18033691). This variant has been reported in another individual affected with colorectal cancer, with the tumor showing high microsatellite instability with loss of MSH2 protein expression (PMID 21671081). This individual carried an additional MSH2 variant of uncertain clinical significance. This variant has also been reported in 2 individuals affected with ovarian cancer (PMID: 19117025), as well as in an individual affected with early-onset breast cancer (PMID: 25503501). This variant has been identified in 10/282854 chromosomes (10 chromosomes in gnomAD non-cancer cohort) in the general population by the Genome Aggregation Database (gnomAD). In summary, this variant has been observed in multiple individuals affected with MSH2-related cancers but has also been reported in unaffected individuals. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656882 SCV000601468 uncertain significance not provided 2020-07-14 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,; 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.
Illumina Clinical Services Laboratory,Illumina RCV000410916 SCV001302499 uncertain significance Lynch syndrome I 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212621 SCV001468270 uncertain significance not specified 2020-12-25 criteria provided, single submitter clinical testing Variant summary: MSH2 c.2503A>C (p.Asn835His) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251448 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2503A>C has been reported in the literature among individuals affected with endometrial cancer with uncertain MSI status (Hampel_2006), a colorectal cancer patient with MSI-low tumor, Tumor IHC positive for MLH1, MSH2, MSH6 (Barneston_2008), breast/ovarian cancer with negative BRCA testing (Maxwell_2014, South_2009, Jarhelle_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2, VUS, n=6) some citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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