ClinVar Miner

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

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Total submissions: 6
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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 The p.T323P variant (also known as c.967A>C), located in coding exon 8 of the CHEK2 gene, results from an A to C substitution at nucleotide position 967. The threonine at codon 323 is replaced by proline, an amino acid with highly similar properties. This alteration has been reported in both breast and prostate cancer cases (LeCalvez-KelmF et al.Breast Cancer Res. 2011 Jan;13(1):R6;Wu X et al.Hum.Mutat. 2006 Aug;27(8):742-7).Functional analysis of this alteration revealed CHEK2-mediated DNA damage response is similar to wild-type; however, this alteration has also been reported to result inpartially reduced CHEK2 kinase activty(RoebW, Higgens J, and King MC. Hum. Mol. Genet. 2012 Jun;21(12):2738-44; Wu X et al.Hum.Mutat. 2006 Aug;27(8):742-7). This residue is located in thealpha-helix of the kinase c-lobe domain; proline substitutions are typically destabilizing to the protein structure in alpha-helix regions (LeCalvez-KelmF et al.Breast Cancer Res. 2011 Jan;13(1):R6).This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 200000alleles tested) in our clinical cohort.This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive.Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
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; Bone osteosarcoma; Malignant tumor of prostate 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000569568 SCV001733905 uncertain significance Hereditary cancer-predisposing syndrome 2021-01-19 criteria provided, single submitter clinical testing This missense variant replaces threonine with proline at codon 323 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant causes a partial loss of CHEK2 kinase activity (PMID: 16835864) but does not affect DNA damage response of the CHEK2 protein (PMID: 22419737). This variant has been observed in individuals affected with early-onset breast caner (PMID: 21244692), familial breast cancer (PMID: 22419737) and prostate cancer (PMID: 16835864). 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.

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