Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000570646 | SCV000661751 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-01-04 | criteria provided, single submitter | clinical testing | The p.K255N variant (also known as c.765G>T), located in coding exon 5 of the CHEK2 gene, results from a G to T substitution at nucleotide position 765. The lysine at codon 255 is replaced by asparagine, an amino acid with similar properties. This variant was observed in an individual diagnosed with two breast cancers, diagnosed at ages 25 and 41 years (Lerner-Ellis J et al. J Cancer Res Clin Oncol. 2021 147, 871–879). 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 this alteration remains unclear. |
| Department of Pathology and Laboratory Medicine, |
RCV001354759 | SCV001549451 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The CHEK2 p.Lys255Asn variant was not identified in the literature nor was it identified in the dbSBP, ClinVar, Cosmic, MutDB, Zhejiang Colon Cancer Database, databases. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The p.Lys255Asn residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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. The variant is located within protein kinase (catalytic) functional domains, increasing the likelihood that it may have clinical significance. 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. |