Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000129825 | SCV000184640 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-12-08 | criteria provided, single submitter | clinical testing | The p.F103L variant (also known as c.307T>C), located in coding exon 1 of the CHEK2 gene, results from a T to C substitution at nucleotide position 307. The phenylalanine at codon 103 is replaced by leucine, an amino acid with highly similar properties. In one study, this alteration was detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). This alteration behaved as functional in an in vivo, yeast-based growth rate assay (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. |
| Invitae | RCV000204150 | SCV000261386 | uncertain significance | Familial cancer of breast | 2024-01-18 | criteria provided, single submitter | clinical testing | This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 103 of the CHEK2 protein (p.Phe103Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 141340). 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. |
| Color Diagnostics, |
RCV000129825 | SCV000684626 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-01-10 | criteria provided, single submitter | clinical testing | This missense variant replaces phenylalanine with leucine at codon 103 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). An experimental functional study demonstrated this variant to be neutral in a yeast based DNA damage repair assay (PMID 30851065) and a complementation study in human cells showed no impact on KAP1 phosphorylation and intermediate impact on CHEK2 autophosphorylation (PMID: 37449874). This variant has been reported in at least two individuals affected with breast cancer (PMID: 29522266, 37449874). 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. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV001800430 | SCV001470503 | uncertain significance | not specified | 2020-12-14 | criteria provided, single submitter | clinical testing |