Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Color Diagnostics, |
RCV000773599 | SCV000907293 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-04-18 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000799463 | SCV000939126 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2018-07-01 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with glutamic acid at codon 3003 of the BRCA2 protein (p.Gly3003Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant has not been reported in the literature in individuals with BRCA2-related disease. Experimental studies for this variant have shown that this missense change causes deficient DNA repair by homologus recombination (PMID: 29394989). 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. |
| Ambry Genetics | RCV000773599 | SCV001179889 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-08-05 | criteria provided, single submitter | clinical testing | The p.G3003E variant (also known as c.9008G>A), located in coding exon 22 of the BRCA2 gene, results from a G to A substitution at nucleotide position 9008. The glycine at codon 3003 is replaced by glutamic acid, an amino acid with similar properties. This variant was non-functional in a homology-directed DNA repair (HDR) assay (Guidugli L et al. Am. J. Hum. Genet., 2018 02;102:233-248; Hart SN et al. Genet. Med., 2019 01;21:71-80; Richardson ME et al. Am J Hum Genet, 2021 Mar;108:458-468). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Cancer Variant Interpretation Group UK, |
RCV000799463 | SCV001478307 | likely pathogenic | Hereditary breast ovarian cancer syndrome | 2018-11-21 | criteria provided, single submitter | curation | Data used in classification: The frequency of this variant is 0/138,632 individuals (gnomAD) (PM2_mod). This variant is predicted deleterious on AlignGVGD (class: C65), SIFT (Deleterious), Polyphen2 HumVar (probably damaging) and CADD (28) (PP3_sup). The variant is in the DNA-binding domain of BRCA2 (PM1_sup). In the VarCall Bayesian statistical model for VUS classification using functional assay data (Guidugli et al Am J Hum Genet 2018; 102:233-248, Couch Lab), the variant has a probability of being deleterious of 0.987 and an overall classification of pathogenic (PS3_strong). Data not used in classification: There are no additional reports of this variant in BIC or BRCA2 LOVD. |
| Baylor Genetics | RCV003472294 | SCV004210411 | uncertain significance | Familial cancer of breast | 2023-01-28 | criteria provided, single submitter | clinical testing | |
| German Consortium for Hereditary Breast and Ovarian Cancer, |
RCV000799463 | SCV005400656 | likely pathogenic | Hereditary breast ovarian cancer syndrome | 2024-10-08 | criteria provided, single submitter | curation | According to the ClinGen ENIGMA BRCA2 v1.1.0 criteria we chose these criteria: PS3 (strong pathogenic): table 9 PS3 met (Richardson), PM2 (supporting pathogenic): Absent from controls in an outbred population, from gnomAD v2.1 (non-cancer, exomeonly subset) and gnomAD v3.1 (non-cancer), PP3 (supporting pathogenic): BayesDEL: 0.351529 |