Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000165105 | SCV000215814 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-04-25 | criteria provided, single submitter | clinical testing | The c.7802A>G variant (also known as p.Y2601C), located in coding exon 15 of the BRCA2 gene, results from an A to G substitution at nucleotide position 7802. The tyrosine at codon 2601 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant leads to an incomplete splice defect in multiple RNA functional studies (Ambry internal data; Fraile-Bethencourt E et al. Front Genet, 2018 May;9:188; Casadei S et al. Proc Natl Acad Sci U S A, 2019 Dec; Degrolard-Courcet E et al. Eur J Hum Genet. 2014 Aug; 22(8):979-87). This alteration was detected in conjunction with a pathogenic BRCA2 frameshift mutation in a family with an atypical Fanconi Anemia presentation in which the FA diagnosis was confirmed by chromosomal breakage analysis of lymphocytes but the physical manifestations were very mild and toxicity to chemotherapy was inconsistent among the confirmed and presumed biallelic siblings (Degrolard-Courcet E et al. Eur J Hum Genet. 2014 Aug; 22(8):979-87). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. In addition, the protein in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. However, because this variant is identified in one or more patients with Fanconi Anemia it may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised. |
| Labcorp Genetics |
RCV000227777 | SCV000283325 | likely pathogenic | Hereditary breast ovarian cancer syndrome | 2024-11-22 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 2601 of the BRCA2 protein (p.Tyr2601Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Fanconi anemia (PMID: 24301060). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 185651). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. Studies have shown that this missense change is associated with altered splicing resulting in unknown protein product (PMID: 24301060, 29881398, 31843900). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| King Laboratory, |
RCV001171447 | SCV001251358 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2; Hereditary breast ovarian cancer syndrome | 2019-09-01 | no assertion criteria provided | research |