Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000223648 | SCV000274611 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2024-02-14 | criteria provided, single submitter | clinical testing | The p.L2721H variant (also known as c.8162T>A), located in coding exon 17 of the BRCA2 gene, results from a T to A substitution at nucleotide position 8162. The leucine at codon 2721 is replaced by histidine, an amino acid with similar properties. This variant was functionally deficient in several assays including homology-directed repair assays and a BRCA2-null mouse embryonic stem cell complementation assay (Karchin R et al. Cancer Inform. 2008;6:203-16; Guidugli L et al. Am. J. Hum. Genet. 2018 Jan; Hart SN et al. Genet. Med., 2019 01;21:71-80; Mesman RLS et al. Genet. Med. 2019; Richardson ME et al. Am J Hum Genet, 2021 Mar;108:458-468). Based on internal structural analysis, this variant is anticipated to result in a decrease in structural stability (Yang H et al. Science 2002 Sep;297:1837-48; Ambry internal data). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Color Diagnostics, |
RCV000223648 | SCV000683948 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-04-03 | criteria provided, single submitter | clinical testing | |
| Cancer Variant Interpretation Group UK, |
RCV001290195 | SCV001478295 | likely pathogenic | Hereditary breast ovarian cancer syndrome | 2018-10-10 | criteria provided, single submitter | curation | Data used in classification: The frequency of this variant is 0/138,632 individuals (gnomAD) (PM2_mod). 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 0.994 and an overall classification of pathogenic. (PS3_strong). Data not used in classification: There are conflicting in silico predictions of pathogenicity; AlignGVGD (class: C25), SIFT (Deleterious), Polyphen2 HumVar (probably damaging) and CADD (19.15). There are additional reports of this variant in ClinVar (3), BIC (1), and BRCA2 LOVD (1). |
| Labcorp Genetics |
RCV001290195 | SCV001535892 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2024-09-30 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 2721 of the BRCA2 protein (p.Leu2721His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 10923033, 35641994). ClinVar contains an entry for this variant (Variation ID: 52513). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 19043619, 29394989, 29988080). 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. |
| Breast Cancer Information Core |
RCV000113878 | SCV000147285 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 2 | 2004-02-20 | no assertion criteria provided | clinical testing |