ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.967A>C (p.Thr323Pro) (rs750984976)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485499 SCV000568300 uncertain significance not provided 2016-07-25 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.967A>C at the cDNA level, p.Thr323Pro (T323P) at the protein level, and results in the change of a Threonine to a Proline (ACC>CCC). This variant was observed in an individual with early-onset breast cancer as well as in both tumor and adjacent normal tissues from an individual with prostate cancer (Dong 2003, Le Calvez-Kelm 2011). In a yeast-based assay CHEK2 Thr323Pro demonstrated DNA damage response comparable to wild-type, but led to partially reduced kinase activity in mammalian cells (Wu 2006, Roeb 2012). CHEK2 Thr323Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Threonine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CHEK2 Thr323Pro occurs at a position that is conserved in mammals and is located in the kinase domain (Desrichard 2011, Roeb 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether CHEK2 Thr323Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000569568 SCV000666364 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-02 criteria provided, single submitter clinical testing Conflicting evidence
Counsyl RCV000663289 SCV000786531 uncertain significance Familial cancer of breast 2018-05-25 criteria provided, single submitter clinical testing
Invitae RCV000663289 SCV000826257 uncertain significance Familial cancer of breast 2019-06-11 criteria provided, single submitter clinical testing This sequence change replaces threonine with proline at codon 323 of the CHEK2 protein (p.Thr323Pro). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with prostate and breast cancer (PMID: 16835864, 22419737, 21244692). ClinVar contains an entry for this variant (Variation ID: 420003). Experimental studies have shown that this missense change demonstrates partially reduced CHEK2 kinase activity, however, DNA damage response was similar to wild-type CHEK2 protein (PMID: 16835864, 22419737). The clinical significance of these findings is uncertain. 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 RCV000765618 SCV000896943 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Osteosarcoma; Malignant tumor of prostate 2018-10-31 criteria provided, single submitter clinical testing

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