ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.499G>C (p.Asp167His) (rs63750255)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115533 SCV000212799 likely benign Hereditary cancer-predisposing syndrome 2018-04-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Intact protein function observed in appropriate functional assay(s),Other data supporting benign classification
CSER_CC_NCGL; University of Washington Medical Center RCV000148629 SCV000190344 likely benign Colorectal cancer, non-polyposis 2014-06-01 no assertion criteria provided research
Color RCV000115533 SCV000690113 likely benign Hereditary cancer-predisposing syndrome 2016-03-10 criteria provided, single submitter clinical testing
GeneDx RCV000200986 SCV000149442 likely benign not specified 2017-09-28 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
GeneKor MSA RCV000115533 SCV000822054 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590114 SCV000696272 likely benign not provided 2016-10-18 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.499G>C (p.Asp167His) variant located in domain II, which connects domain I to the body of the MSH2 clamp (Heinen_2002) causes a missense change involving a conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging, however, multiple functional studies have performed with conflicting findings. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 13/121412 (1/9337, 1 homozygote), which does not exceed the estimated maximal expected allele frequency for a pathogenic MSH2 variant of 1/1759. The variant of interest has een reported in multiple affected individuals via publications, in which co-occurrences were reported with a pathogenic MLH1 variant, 21delG, c.1852_1854delAAG (p.Lys618del - classified as pathogenic by LCA), and a MSH6 variant, c.2405delC (p.Pro802LeufsX7), which IHC staining indicated the presence of MSH2 protein, however, MLH1 was absent. In addition, multiple reputable databases/clinical diagnostic laboratories cite the variant as "likely benign/benign." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as "Likely Benign."
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076615 SCV000107651 benign Lynch syndrome I 2018-06-13 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability < 0.001 (0.000015)
Invitae RCV000524411 SCV000218857 benign Hereditary nonpolyposis colon cancer 2017-12-27 criteria provided, single submitter clinical testing

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