ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.415T>C (p.Tyr139His)

dbSNP: rs730881703
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000568786 SCV000666384 uncertain significance Hereditary cancer-predisposing syndrome 2024-01-31 criteria provided, single submitter clinical testing The p.Y139H variant (also known as c.415T>C), located in coding exon 2 of the CHEK2 gene, results from a T to C substitution at nucleotide position 415. The tyrosine at codon 139 is replaced by histidine, an amino acid with similar properties. This alteration was reported as functionally impaired in a study assessing CHEK2-complementation through quantification of KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells (Stolarova L et al. Clin Cancer Res, 2023 Aug;29:3037-3050). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV000796300 SCV000935806 uncertain significance Familial cancer of breast 2024-08-11 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 139 of the CHEK2 protein (p.Tyr139His). 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: 481729). 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.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne RCV004689796 SCV005184343 likely pathogenic Hereditary breast ovarian cancer syndrome 2024-05-03 criteria provided, single submitter curation According to the ACMG SVI adaptation criteria we chose these criteria: PS3 (strong pathogenic): Stolarova 2023: KAP1 und CHK2 assay damaging, PM2 (supporting pathogenic): absent from controls (gnomAD v2/3), PP3 (supporting pathogenic): REVEL: 0.757 (cutoff > 0.733)

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