ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.742A>G (p.Ile248Val) (rs779457035)

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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 RCV000492498 SCV000581175 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000492498 SCV000689718 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-04 criteria provided, single submitter clinical testing
Counsyl RCV000198756 SCV000786162 uncertain significance Familial cancer of breast 2018-03-12 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765621 SCV000896946 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Osteosarcoma; Malignant tumor of prostate 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000484098 SCV000568935 uncertain significance not provided 2017-09-15 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.742A>G at the cDNA level, p.Ile248Val (I248V) at the protein level, and results in the change of an Isoleucine to a Valine (ATA>GTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Ile248Val was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. CHEK2 Ile248Val occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is located in the kinase domain (Cai 2009, Roeb 2012). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether CHEK2 Ile248Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000198756 SCV000254951 uncertain significance Familial cancer of breast 2018-11-29 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 248 of the CHEK2 protein (p.Ile248Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs779457035, 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: 216651). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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