ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1000G>A (p.Ala334Thr)

dbSNP: rs864622371
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205766 SCV000260332 uncertain significance Familial cancer of breast 2024-01-27 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 334 of the CHEK2 protein (p.Ala334Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 26921362). ClinVar contains an entry for this variant (Variation ID: 220075). 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. 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.
Ambry Genetics RCV000234858 SCV000276830 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-14 criteria provided, single submitter clinical testing The p.A334T variant (also known as c.1000G>A), located in coding exon 8 of the CHEK2 gene, results from a G to A substitution at nucleotide position 1000. The alanine at codon 334 is replaced by threonine, an amino acid with similar properties. This variant has been previously reported in two individuals with breast cancer (Easton DF et al. J Med Genet, 2016 05;53:298-309). In an in vivo, yeast-based growth rate assay, this alteration behaved as functional (Delimitsou A et al. Hum Mutat, 2019 05;40:631-648). 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.
Color Diagnostics, LLC DBA Color Health RCV000234858 SCV000292189 uncertain significance Hereditary cancer-predisposing syndrome 2023-01-24 criteria provided, single submitter clinical testing This missense variant replaces alanine with threonine at codon 334 of the CHEK2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported 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.
GeneDx RCV001582710 SCV001812945 uncertain significance not provided 2019-12-06 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies demonstrate no damaging effect: normal growth after MMS-induced DNA damage (Delimitsou 2019); This variant is associated with the following publications: (PMID: 30851065, 26921362, 28825729)
Sema4, Sema4 RCV000234858 SCV002537011 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-27 criteria provided, single submitter curation

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