Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001017462 | SCV001178546 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-07-01 | criteria provided, single submitter | clinical testing | The p.T383A variant (also known as c.1147A>G), located in coding exon 10 of the CHEK2 gene, results from an A to G substitution at nucleotide position 1147. The threonine at codon 383 is replaced by alanine, an amino acid with similar properties. This variant was observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome; however, this individual also carried a pathogenic BRCA1 mutation (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This alteration has also been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). In phosphorylation assays, this alteration showed dramatically reduced kinase activity (Guo X et al. J Biol Chem, 2010 Oct;285:33348-33357; Lee CH et al. J Biol Chem, 2001 Aug;276:30537-41). 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. |
| Myriad Genetics, |
RCV003336249 | SCV004044327 | likely pathogenic | Familial cancer of breast | 2023-06-28 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 11390408, 20713355]. |
| Department of Pathology and Laboratory Medicine, |
RCV001355097 | SCV001549872 | uncertain significance | Malignant tumor of breast | no assertion criteria provided | clinical testing | The CHEK2 p.Thr383Ala variant was not identified in the literature nor was it identified in the ClinVar database. The variant was identified in dbSNP (ID: rs769439021) as "NA". The variant was identified in control databases in 1 of 245892 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European Non-Finnish in 1 of 111376 chromosomes (freq: 0.000009), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Thr383 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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. |