ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.436A>C (p.Ile146Leu)

gnomAD frequency: 0.00001  dbSNP: rs781678896
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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 RCV000570860 SCV000661728 uncertain significance Hereditary cancer-predisposing syndrome 2022-10-19 criteria provided, single submitter clinical testing The p.I146L variant (also known as c.436A>C), located in coding exon 2 of the CHEK2 gene, results from an A to C substitution at nucleotide position 436. The isoleucine at codon 146 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV000570860 SCV000684639 uncertain significance Hereditary cancer-predisposing syndrome 2023-06-27 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with leucine at codon 146 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 2/60466 cases and 3/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID CHEK2_000226). This variant has been identified in 3/251306 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae RCV000635731 SCV000757153 uncertain significance Familial cancer of breast 2023-10-05 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 146 of the CHEK2 protein (p.Ile146Leu). This variant is present in population databases (rs781678896, gnomAD 0.003%). 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: 479549). 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 tolerated. 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.
Fulgent Genetics, Fulgent Genetics RCV000765624 SCV000896949 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Bone osteosarcoma; Malignant tumor of prostate 2018-10-31 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001800767 SCV002047198 uncertain significance not provided 2023-07-18 criteria provided, single submitter clinical testing In the published literature, this variant has been reported in individuals undergoing hereditary cancer panel testing (PMID: 32906215 (2020)), as well as in breast cancer cases and control individuals in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/CHEK2)). The frequency of this variant in the general population, 0.000026 (3/113604 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Baylor Genetics RCV000635731 SCV004217573 uncertain significance Familial cancer of breast 2023-09-05 criteria provided, single submitter clinical testing

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