ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.514A>G (p.Thr172Ala)

dbSNP: rs786203836
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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 RCV000167316 SCV000218164 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-06 criteria provided, single submitter clinical testing The p.T172A variant (also known as c.514A>G), located in coding exon 3 of the CHEK2 gene, results from an A to G substitution at nucleotide position 514. The threonine at codon 172 is replaced by alanine, an amino acid with similar properties. This variant was reported in 1 of 673 sporadic breast cancer patients and was not reported in 683 non-cancer controls (Kleibl Z, Breast Cancer Res. Treat. 2008 Nov; 112(1):159-64). This alteration behaved as functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum Mutat, 2019 May;40:631-648). This amino acid position is poorly 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586115 SCV000698809 uncertain significance not provided 2016-09-30 criteria provided, single submitter clinical testing Variant summary: The c.514A>G (p.Thr172Ala) in CHEK2 gene is a missense change that involves a non-conserved nucleotide and 3/4 in silico tools predict benign outcome and this change could be tolerated based on conservation analysis. The variant of interest is located within highly conserved FHA domain, although the functional impact of this missense change is yet to be studied. The variant is absent from the large control population dataset of ExAC. The variant has been reported in 1 sporadic BrC case without strong evidence for causality (Kleibl, 2008). In addition, it was cited as VUS by a reputable database/clinical laboratory. Taken together, the variant was classified as VUS until more data becomes available.
Color Diagnostics, LLC DBA Color Health RCV000167316 SCV000913596 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-22 criteria provided, single submitter clinical testing
Invitae RCV000820411 SCV000961122 uncertain significance Familial cancer of breast 2023-09-20 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 172 of the CHEK2 protein (p.Thr172Ala). This variant is present in population databases (rs786203836, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 18058223). ClinVar contains an entry for this variant (Variation ID: 187576). 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. Experimental studies have shown that this missense change does not substantially affect CHEK2 function (PMID: 30851065). 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.
Baylor Genetics RCV000820411 SCV004217530 uncertain significance Familial cancer of breast 2023-09-29 criteria provided, single submitter clinical testing

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