Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000217761 | SCV000276433 | uncertain significance | Hereditary cancer-predisposing syndrome | 2015-06-08 | criteria provided, single submitter | clinical testing | The p.L277F variant (also known as c.831G>C), located in coding exon 6 of the CHEK2 gene, results from a G to C substitution at nucleotide position 831. The leucine at codon 277 is replaced by phenylalanine, 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 6492 samples (12984 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 nucleotide position is highly conserved in available vertebrate species. 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 p.L277F remains unclear. |
Invitae | RCV001853586 | SCV002266379 | uncertain significance | Familial cancer of breast | 2022-07-29 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 232325). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 277 of the CHEK2 protein (p.Leu277Phe). |
Color Diagnostics, |
RCV000217761 | SCV004361375 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-10-11 | criteria provided, single submitter | clinical testing | This missense variant replaces leucine with phenylalanine at codon 277 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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. |