ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1318A>C (p.Ile440Leu)

dbSNP: rs587780176
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115997 SCV000149906 uncertain significance not provided 2022-09-26 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22419737, 19782031)
Color Diagnostics, LLC DBA Color Health RCV000234920 SCV000292197 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000234920 SCV000669248 uncertain significance Hereditary cancer-predisposing syndrome 2021-06-28 criteria provided, single submitter clinical testing The p.I440L variant (also known as c.1318A>C), located in coding exon 11 of the CHEK2 gene, results from an A to C substitution at nucleotide position 1318. The isoleucine at codon 440 is replaced by leucine, an amino acid with highly similar properties. This alteration has been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000796599 SCV000936119 uncertain significance Familial cancer of breast 2024-01-27 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 440 of the CHEK2 protein (p.Ile440Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 128057). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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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