Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000223071 | SCV000277751 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-05-24 | criteria provided, single submitter | clinical testing | The p.F447C variant (also known as c.1340T>G), located in coding exon 11 of the CHEK2 gene, results from a T to G substitution at nucleotide position 1340. The phenylalanine at codon 447 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was also observed in 1/3251 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 amino acid position is not well 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. |
| Invitae | RCV001854691 | SCV002166205 | uncertain significance | Familial cancer of breast | 2021-11-15 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 233388). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 447 of the CHEK2 protein (p.Phe447Cys). |
| Sema4, |
RCV000223071 | SCV002537049 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-02-05 | criteria provided, single submitter | curation | |
| Department of Pathology and Laboratory Medicine, |
RCV001354931 | SCV001549660 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The CHEK2 p.Phe447Cys variant was not identified in the literature nor was it identified in the following databases: dbSNP, Cosmic, MutDB, Zhejiang Colon Cancer Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016). The variant was identified in ClinVar (as uncertain significance by Ambry Genetics), and Clinvitae (1x). The p.Phe447 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The 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. |