Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Evidence- |
RCV000112381 | SCV001161640 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2019-06-18 | reviewed by expert panel | curation | IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.999912 |
| Invitae | RCV000205534 | SCV000259258 | likely pathogenic | Hereditary breast ovarian cancer syndrome | 2015-07-02 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Likely Pathogenic. Truncating variants in BRCA1 are known to be pathogenic. This particular truncation has been reported in an individual with triple negative breast cancer (PMID: 25452441). This sequence change affects an acceptor splice site in intron 14. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. |
| Consortium of Investigators of Modifiers of BRCA1/2 |
RCV000112381 | SCV000326027 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2015-10-02 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV000563564 | SCV000660950 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-05-05 | criteria provided, single submitter | clinical testing | The c.4676-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 14 of the BRCA1 gene. This alteration has been reported as a likely deleterious mutation in at least one patient with triple negative breast cancer (Couch FJ et al. J Clin Oncol. 2015 Feb 1;33(4):304-11; Hoyer J et al. BMC Cancer, 2018 Sep;18:926). This variant was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 May;39:593-620). This alteration was also classified as pathogenic in a multifactorial model of variant interpretation that incorporates co-segregation, family history, co-occurrence and tumor pathology and case-control data (Parsons MT et al. Hum Mutat, 2019 Sep;40:1557-1578). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. |
| Color Diagnostics, |
RCV000563564 | SCV001359511 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-06-15 | criteria provided, single submitter | clinical testing | This variant causes a G to A nucleotide substitution at the -1 position of intron 14 of the BRCA1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in three individuals affected with breast cancer (PMID: 11448907, 25452441). A multifactorial analysis reported likelihood ratios for pathogenicity based on segregation, co-occurrence with a pathogenic covariant and family history of 3.7504, 2.0153 and 32.3133, respectively (PMID: 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. |
| Breast Cancer Information Core |
RCV000112381 | SCV000145153 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 1999-06-21 | no assertion criteria provided | clinical testing | |
| CZECANCA consortium | RCV001271028 | SCV001451842 | pathogenic | Breast and/or ovarian cancer | 2019-06-11 | no assertion criteria provided | clinical testing |