ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1178C>T (p.Pro393Leu)

gnomAD frequency: 0.00001  dbSNP: rs730881690
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160434 SCV000210985 uncertain significance not provided 2021-04-29 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV000576132 SCV000669239 uncertain significance Hereditary cancer-predisposing syndrome 2021-12-08 criteria provided, single submitter clinical testing The p.P393L variant (also known as c.1178C>T), located in coding exon 10 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1178. The proline at codon 393 is replaced by leucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000704401 SCV000833349 uncertain significance Familial cancer of breast 2024-01-18 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 393 of the CHEK2 protein (p.Pro393Leu). 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: 182435). 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.
Fulgent Genetics, Fulgent Genetics RCV000764374 SCV000895409 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
Color Diagnostics, LLC DBA Color Health RCV000576132 SCV000913581 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-01 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 393 of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
Baylor Genetics RCV000704401 SCV004217570 uncertain significance Familial cancer of breast 2023-09-06 criteria provided, single submitter clinical testing

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