ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1790A>C (p.Asp597Ala) (rs548407418)

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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 RCV000162476 SCV000212849 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000761052 SCV000890967 uncertain significance High Grade Surface Osteosarcoma 2016-07-20 no assertion criteria provided clinical testing
Color RCV000162476 SCV000292190 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-04 criteria provided, single submitter clinical testing
Counsyl RCV000409730 SCV000489409 uncertain significance Lynch syndrome I 2016-10-03 criteria provided, single submitter clinical testing
GeneDx RCV000480972 SCV000566598 uncertain significance not provided 2018-10-02 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1790A>C at the cDNA level, p.Asp597Ala (D597A) at the protein level, and results in the change of an Aspartic Acid to an Alanine (GAT>GCT). This variant has been observed in a pediatric leukemia patient (Zhang 2015). MSH2 Asp597Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH2 Asp597Ala is located within the lever domain and the region that interacts with MSH6 and MSH3 (Guerrette 1998, Lutzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Asp597Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000781560 SCV000919704 uncertain significance not specified 2018-05-18 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1790A>C (p.Asp597Ala) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 246236 control chromosomes. This frequency is not higher than expected for a pathogenic variant in MSH2 causing Lynch Syndrome (1.6e-05 vs 0.00057), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1790A>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000167995 SCV000218645 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with alanine at codon 597 of the MSH2 protein (p.Asp597Ala). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and alanine. This variant is present in population databases (rs548407418, ExAC 0.009%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 183758). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Mendelics RCV000708834 SCV000837839 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000480972 SCV000889426 uncertain significance not provided 2017-09-12 criteria provided, single submitter clinical testing

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