Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000217340 | SCV000272935 | likely benign | Hereditary cancer-predisposing syndrome | 2019-04-26 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
| Gene |
RCV000237043 | SCV000292503 | uncertain significance | not provided | 2016-02-22 | criteria provided, single submitter | clinical testing | This variant is denoted BRCA1 c.593+4A>G or IVS8+4A>G and consists of an A>G nucleotide substitution at the +4 position of intron 8 of the BRCA1 gene. Multiple in silico models predict this variant to weaken the nearby natural donor site, and to possibly cause abnormal gene splicing. An in vitro splicing assay found that this variant results in deletion of exon 9; however, there is suggestion that deletion of exon 9 is a natural isoform in some tissues (Whiley 2011). The variant, also published as BRCA1 712+4A>G using alternate nomenclature, was predicted by Lindor et al. (2012) to be neutral based on tumor pathology, clinical histories, family studies and co-occurrence with deleterious mutations. BRCA1 c.593+4A>G was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The adenine (A) nucleotide that is altered is not conserved. Based on currently available information, it is unclear whether BRCA1 c.593+4A>G is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
| Color Diagnostics, |
RCV000217340 | SCV001345466 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-05-16 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001297373 | SCV001486385 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2024-01-10 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 8 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with breast cancer (PMID: 21394826, 31465090). ClinVar contains an entry for this variant (Variation ID: 55643). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a low probability of being pathogenic (PMID: 21394826). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Loss-of-function variants in BRCA1 are expected to be pathogenic (PMID: 20104584). However, an in-frame BRCA1 isoform lacking exons 8 and 9 (also known as exons 9 and 10) is highly expressed in blood from unaffected individuals and in normal breast tissue; this isoform may retain protein function and could functionally rescue loss-of-function variants within exons 8-9 (PMID: 24569164). 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 |
RCV000112748 | SCV000145635 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 1 | 2003-12-23 | no assertion criteria provided | clinical testing |