ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1032A>G (p.Ile344Met)

gnomAD frequency: 0.00001  dbSNP: rs202051128
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214665 SCV000276727 uncertain significance Hereditary cancer-predisposing syndrome 2023-06-20 criteria provided, single submitter clinical testing The p.I344M variant (also known as c.1032A>G), located in coding exon 9 of the CHEK2 gene, results from an A to G substitution at nucleotide position 1032. The isoleucine at codon 344 is replaced by methionine, an amino acid with highly similar properties. This variant has been reported with a carrier frequency of 0.00057 in 7,051 unselected breast cancer patients and 0.00036 in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). In another study, this variant was reported in 0/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant has also been reported in 1/416 papillary thyroid carcinoma patients and 0/100 healthy controls (Shen CT et al. Endocrine, 2019 06;64:622-631). 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.
GeneDx RCV000759771 SCV000567295 uncertain significance not provided 2022-03-02 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; Observed in individuals with breast cancer as well as in unaffected controls in published literature (Momozawa 2018).; This variant is associated with the following publications: (PMID: 30287823, 22419737, 19782031)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759771 SCV000889321 uncertain significance not provided 2022-12-08 criteria provided, single submitter clinical testing The frequency of this variant in the general population, 0.00035 (7/19946 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer as well as in several healthy controls (PMID: 30287823 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Invitae RCV000807751 SCV000947822 uncertain significance Familial cancer of breast 2024-01-14 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 344 of the CHEK2 protein (p.Ile344Met). This variant is present in population databases (rs202051128, gnomAD 0.04%). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 232564). 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.
Color Diagnostics, LLC DBA Color Health RCV000214665 SCV001351703 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-12 criteria provided, single submitter clinical testing

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