Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000220253 | SCV000275824 | uncertain significance | Hereditary cancer-predisposing syndrome | 2015-05-16 | criteria provided, single submitter | clinical testing | The p.L174V variant (also known as c.520C>G), located in coding exon 3 of the CHEK2 gene, results from a C to G substitution at nucleotide position 520. The leucine at codon 174 is replaced by valine, an amino acid with highly similar properties. 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 6502 samples (13004 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 72000 alleles tested) in our clinical cohort. This amino acid position is 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 p.L174V remains unclear. |
| Invitae | RCV001853562 | SCV002131054 | uncertain significance | Familial cancer of breast | 2022-04-01 | criteria provided, single submitter | clinical testing | Experimental studies have shown that this missense change affects CHEK2 function (PMID: 31050813, 31409080). 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: "Benign"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 231849). This missense change has been observed in individual(s) with breast cancer (PMID: 31050813). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 174 of the CHEK2 protein (p.Leu174Val). |