Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000637721 | SCV000759194 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2023-10-04 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 1746 of the BRCA1 protein (p.His1746Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ovarian cancer (PMID: 25036526). ClinVar contains an entry for this variant (Variation ID: 531399). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 11877378, 30209399, 30765603). 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 | RCV002334088 | SCV002645354 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-02-07 | criteria provided, single submitter | clinical testing | The p.H1746D variant (also known as c.5236C>G), located in coding exon 18 of the BRCA1 gene, results from a C to G substitution at nucleotide position 5236. The histidine at codon 1746 is replaced by aspartic acid, an amino acid with similar properties. This variant has been reported in an individual diagnosed with ovarian cancer and in a cohort of Chinese individuals who underwent multi-gene panel testing for HBOC risk assessment (Gleicher N et al. PLoS One, 2014 Jul;9:e102370; Shao D et al. Cancer Sci, 2020 Feb;111:647-657). One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). A transcription activation assay found that this variant had <80% activity relative to wildtype and was, thus, considered deleterious (Fernandes VC et al. J Biol Chem, 2019 04;294:5980-5992). Based on internal structural analysis, this variant is anticipated to result in a decrease in structural stability (Ambry internal data; Wu Q et al. Mol Cell, 2016 Feb;61:434-448). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV003478362 | SCV004219448 | uncertain significance | not provided | 2022-10-21 | criteria provided, single submitter | clinical testing | It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an individual with ovarian cancer (PMID: 25036526 (2014)). Functional studies are supportive of a damaging effect on protein function (PMIDs: 30765603 (2019), 30209399 (2018), 11877378 (2002)), however additional studies are needed to determine the global effect of this variant on BRCA1 protein function. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. |
| German Consortium for Hereditary Breast and Ovarian Cancer, |
RCV000637721 | SCV004227976 | likely pathogenic | Hereditary breast ovarian cancer syndrome | 2023-11-14 | criteria provided, single submitter | curation | PS3, PM2_sup, PP3. According to the ClinGen ENIGMA BRCA1 v1.0.0 criteria we chose these criteria: PS3 (strong pathogenic): PS3_strong:Table 9: Reported by two calibrated studies to affect protein function similar to pathogenic control variants (PMIDs:30209399, Findlay, 30765603, Fernandes), PM2 (supporting pathogenic): Absent from gnomAD PM2_supp, PP3 (supporting pathogenic): BayesDel noAF score 0.3731 |
| Brotman Baty Institute, |
RCV001072554 | SCV001237959 | not provided | Breast-ovarian cancer, familial, susceptibility to, 1 | no assertion provided | in vitro |