ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1690A>G (p.Thr564Ala) (rs55778204)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000564309 SCV000662216 likely benign Hereditary cancer-predisposing syndrome 2017-11-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with mutation in same gene (phase unknown),Other data supporting benign classification
Center for Human Genetics, Inc RCV000659881 SCV000781773 uncertain significance Lynch syndrome I 2016-11-01 criteria provided, single submitter clinical testing
Color RCV000564309 SCV000910721 likely benign Hereditary cancer-predisposing syndrome 2015-11-03 criteria provided, single submitter clinical testing
GeneDx RCV000445069 SCV000515767 likely benign not specified 2017-08-21 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.
Integrated Genetics/Laboratory Corporation of America RCV000589504 SCV000696223 benign not provided 2017-02-02 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.1690A>G (p.Thr564Ala) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPs&GO and Mutation Taster not captured due to low reliability index). This variant was found in 22/120830 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.002547 (22/8638). This frequency is about 4 times the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. The variant was found in several studies assessing colorectal cancer patients with normal IHC and microsatellite stable tumors; however no strong evidence for pathogenicity were present. Furthermore, in one family the variant did not co-segregate with the disease, and the cause of cancer in this family was attributed to a pathogenic variant in the APC gene, further supporting a neutral outcome. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Considering all evidence, the variant is classified as Benign.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076247 SCV000107266 no known pathogenicity Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability <0.001
Invitae RCV000524355 SCV000166266 likely benign Hereditary nonpolyposis colon cancer 2017-12-22 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000445069 SCV000539681 likely benign not specified 2016-12-02 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been seen in 0.25% of East Asian chrs (0.31% in gnomAD - too high for disease frequency). It is classified in ClinVar with 3 stars as benign by an expert panel (InSiGHT) and Invitae. It has been reported in 3 papers: in one it did not segregate in the family with disease, in one it was predicted to be not pathogenic, and one where MSH2 expression was retained. Rabbit also has an Alanine at this position.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000445069 SCV000601436 likely benign not specified 2016-07-22 criteria provided, single submitter clinical testing

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