ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.549G>C (p.Leu183Phe) (rs745646057)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164270 SCV000214895 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
University of Washington Department of Laboratory Medicine,University of Washington RCV000210079 SCV000266169 uncertain significance Breast and colorectal cancer, susceptibility to 2015-11-20 criteria provided, single submitter clinical testing
GeneDx RCV000221179 SCV000279299 uncertain significance not provided 2015-12-03 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.549G>C at the cDNA level, p.Leu183Phe (L183F) at the protein level, and results in the change of a Leucine to a Phenylalanine (TTG>TTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Leu183Phe was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Phenylalanine share similar properties, this is considered a conservative amino acid substitution. CHEK2 Leu183Phe occurs at a position that is conserved across species and is located within the FHA domain (Roeb 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether CHEK2 Leu183Phe is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000459747 SCV000550501 uncertain significance Familial cancer of breast 2018-12-06 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 183 of the CHEK2 protein (p.Leu183Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs745646057, ExAC 0.001%). This variant has not been reported in the literature in individuals with CHEK2-related disease. ClinVar contains an entry for this variant (Variation ID: 184928). 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: "Probably Damaging"; Align-GVGD: "Class C15"). 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 RCV000459747 SCV000785293 uncertain significance Familial cancer of breast 2017-06-29 criteria provided, single submitter clinical testing
Color RCV000164270 SCV000903187 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-07 criteria provided, single submitter clinical testing

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