Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The c.5073A>G variant in BRCA1 is a synonymous variant (p.Thr1691=). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA1 silent variant has a SpliceAI predictor score of 0.71, predicting an impact on splicing (score threshold >0.20) (PP3 met). Although this variant was reported by one calibrated study to exhibit protein function similar to benign control variants, other silent variants at the same position (c.5073A>C/T) were reported to affect function similar to pathogenic control variants in the same assay (PMID:30209399). Additionally, these three variants have the same predicted effect on splicing and a splicing impact was observed for variant c.5073A>G (Ambry personal communication) (BS3 not applied due to conflicting evidence). In summary, this variant meets the criteria to be classified as a Variant of uncertain significance for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3). LINK:https://erepo.genome.network/evrepo/ui/classification/CA003191/MONDO:0011450/092
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Other:1
not provided, no classification provided
in vitro
Brotman Baty Institute, University of Washington
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Uncertain significance, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
Mar 14, 2002
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BRCA1-related cancer predisposition Uncertain:1
Uncertain significance, reviewed by expert panel
curation
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen
Jun 11, 2024
The c.5073A>G variant in BRCA1 is a synonymous variant (p.Thr1691=). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth >=25) and gnomAD v3.1 (non-cancer subset, read depth >=25) (PM2_Supporting met). This BRCA1 silent variant has a SpliceAI predictor score of 0.71, predicting an impact on splicing (score threshold >0.20) (PP3 met). Although this variant was reported by one calibrated study to exhibit protein function similar to benign control variants, other silent variants at the same position (c.5073A>C/T) were reported to affect function similar to pathogenic control variants in the same assay (PMID: 30209399). Additionally, these three variants have the same predicted effect on splicing and a splicing impact was observed for variant c.5073A>G (Ambry personal communication) (BS3 not applied due to conflicting evidence). In summary, this variant meets the criteria to be classified as a Variant of uncertain significance for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3). -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
Jul 09, 2014
This variant is denoted BRCA1 c.5073A>G at the DNA level. Although the variant is silent at the coding level, preserving a Threonine at codon 1691, multiple in silico models predict this variant to negatively impact the nearby natural splice donor site, and to possibly cause abnormal gene splicing. This variant, also known as BRCA1 c.5192A>G by alternate nomenclature, was shown to exhibit loss of function when studied by a transcription activation assay (Carvalho 2002). BRCA1 c.5073A>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 nucleotide which is altered, an adenine (A) at base 5073, is well conserved across mammals. Based on currently available information, it is unclear whether BRCA1 c.5073A>G is pathogenic or benign. We consider it to be a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter
clinical testing
Ambry Genetics
Mar 04, 2022
The c.5073A>G variant (also known as p.T1691T), located in coding exon 15, results from an A to G substitution at nucleotide position 5073 of the BRCA1 gene. This nucleotide substitution does not change the amino acid at codon 1691. However, this change occurs in the second to last base pair of coding exon 15, which gives it potential to have some effect on normal mRNA splicing. This alteration (designated as 5192A>G) exhibited loss of function when studied by a transcriptional activation assay in yeast, but was also reported as functional in a high throughput, genome editing, haploid cell survival assay (Carvalho MA et al. Cancer Biol.Ther. 2002 Sep;1(5):502-8; Findlay GM et al. Nature, 2018 10;562:217-222). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site, however, direct evidence is insufficient at this time (Ambry internal data). A different alteration at this location, c.5073A>T, also predicted to weaken the native donor site, has been reported as having a splicing impact in the literature, producing two aberrant transcripts, one resulting in skipping of coding exon 15, and one with a partial inclusion of intron 15 (Coppa A et al. Cancer Med, 2018 01;7:46-55). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Oct 08, 2023
This sequence change affects codon 1691 of the BRCA1 mRNA. It is a 'silent' change, meaning that it does not 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 not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 55374). Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (PMID: 30209399; Invitae). 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. -