ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1141A>G (p.Met381Val) (rs375130261)

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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 RCV000129242 SCV000184000 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-26 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000212452 SCV000210984 uncertain significance not provided 2018-03-16 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.1141A>G at the cDNA level, p.Met381Val (M381V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has been observed in at least one individual with early-onset colorectal cancer (DeRycke 2017). Although this variant was observed in large population cohorts, population data in this region of CHEK2 are not considered reliable due to high pseudogene homology (Lek 2016). This variant is located within the protein kinase domain (Cai 2009, Roeb 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether CHEK2 Met381Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000227000 SCV000289647 uncertain significance Familial cancer of breast 2019-12-26 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 381 of the CHEK2 protein (p.Met381Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs375130261, ExAC 0.005%). This variant has been observed in an individual affected with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 140959). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Counsyl RCV000227000 SCV000488278 uncertain significance Familial cancer of breast 2016-02-16 criteria provided, single submitter clinical testing
Color RCV000129242 SCV000537598 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-14 criteria provided, single submitter clinical testing
Mendelics RCV000227000 SCV000839465 uncertain significance Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212452 SCV000888097 uncertain significance not provided 2018-07-12 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764375 SCV000895410 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Osteosarcoma; Malignant tumor of prostate 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781303 SCV000919223 uncertain significance not specified 2018-08-13 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.1141A>G (p.Met381Val) results in a conservative amino acid change located in the Protein kinase domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 276850 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer (4e-05 vs 0.00031), allowing no conclusion about variant significance. c.1141A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Tung_2014). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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