Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000469556 | SCV000550545 | uncertain significance | Familial cancer of breast | 2023-10-27 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 92 of the CHEK2 protein (p.Pro92Leu). This variant is present in population databases (rs779269031, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 26976419). ClinVar contains an entry for this variant (Variation ID: 410059). 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. 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 | RCV000572603 | SCV000666339 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-08-10 | criteria provided, single submitter | clinical testing | The p.P92L variant (also known as c.275C>T), located in coding exon 1 of the CHEK2 gene, results from a C to T substitution at nucleotide position 275. The proline at codon 92 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in a cohort of 488 patients with stages I to III breast cancer who were tested with a 25-gene panel test (Tung N et al. J Clin Oncol, 2016 May;34:1460-8). This variant was also observed in 2/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This alteration was reported as functional 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 Jul;:OF1-OF14). 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 limited at this time, the clinical significance of this alteration remains unclear. |
| Color Diagnostics, |
RCV000572603 | SCV001339590 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-04-30 | criteria provided, single submitter | clinical testing | |
| Department of Pathology and Laboratory Medicine, |
RCV001358000 | SCV001553623 | uncertain significance | Malignant tumor of breast | no assertion criteria provided | clinical testing | The CHEK2 p.Pro92Leu variant was identified in 1 of 976 proband chromosomes (frequency: 0.001) from individuals or families with stage I to III breast cancer and was listed as uncertain significance in this study (Tung 2016). The variant was also identified in dbSNP (ID: rs779269031) as “With Uncertain significance”, ClinVar (1x, as uncertain significance, by Invitae), Clinvitae (1x as uncertain significance), Cosmic (reported 2x, in skin with malignant melanoma and carcinoma). The variant was not identified in MutDB or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 4 of 246194 chromosomes at a frequency of 0.000016 (Genome Aggregation Consortium Feb 27, 2017)". In addition the p.Pro92 variant was identified with a different substitution and amino acid consequence (c.275C>G, p.Pro329Arg), in the literature in a cohort of BRCA1/2-negative early-onset and familial breast and/or ovarian cancer patients from Pakistan, as potentially deleterious (Rashid 2013). The p.Pro92Arg variant was not identified in control databases. The p.Pro92 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The c.275C>T variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. |