Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The ENST00000357654.9(BRCA1):c.132C>T(p.Cys44=) variant causes a splice region, synonymous change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
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]
Verdict is Pathogenic. Variant got 11 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Multiple lines of computational evidence support a deleterious effect 4: Cadd, dbscSNV1_ADA, dbscSNV1_RF, max_spliceai [when BayesDel_noAF, Dann was below the threshold]
PP5
Variant 17-43115728-G-A is Pathogenic according to our data. Variant chr17-43115728-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 230061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43115728-G-A is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter
clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Oct 02, 2015
- -
not provided, no classification provided
in vitro
Brotman Baty Institute, University of Washington
-
- -
Pathogenic, criteria provided, single submitter
clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
May 27, 2024
PVS1 (RNA); PS3; PM2_Supporting -
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
May 14, 2024
The BRCA1 c.132C>T (p.Cys44=) synonymous variant has been reported in the published literature in several individuals with breast and/or ovarian cancer (PMIDs: 35864222 (2022), 35087763 (2021), 34120093 (2021), 32803532 (2020)). RNA studies indicate this variant causes aberrant splicing and alters the reading frame of the BRCA1 mRNA, resulting in disrupted protein synthesis (PMIDs: 35087763 (2021), 24667779 (2014)). In addition, saturation genome editing assays measuring DNA repair-dependent cell survival characterized this variant as being non-functional (PMIDs: 32803532 (2020), 30209399 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter
clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Likely pathogenic, criteria provided, single submitter
clinical testing
Ambry Genetics
Nov 24, 2021
The c.132C>T variant (also known as p.C44C), located in coding exon 2 of the BRCA1 gene, results from a C to T substitution at nucleotide position 132. This nucleotide substitution does not change the cysteine at codon 44. One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). This alteration has been identified in two individuals with ovarian cancer from one family (Wang K et al. Cancer Genet, 2021 Aug;256-257:127-130) as well as in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. A splicing reporter minigene assay showed that this alteration led to the use of a cryptic splice site 4 base pairs upstream of the native donor splice site resulting in the loss of the last 4 base pairs of the exon (Steffensen AY et al. Eur J Hum Genet, 2014 Dec;22:1362-8). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Likely pathogenic, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Aug 28, 2023
This synonymous variant causes a C>T nucleotide change in exon 3 of the BRCA1 gene. Splice site prediction tools indicate that this variant may create a cryptic splice donor sites 4 nucleotides upstream of the native intron 3 splice donor site. RNA studies on carrier RNA and in minigene-splicing assays have detected an aberrant mRNA transcript lacking the last 4 nucleotides of exon 3 that is predicted to result in absent protein product (PMID: 24667779, 34120093, 35087763). A functional study has reported that this variant impacts BRCA1 function in a haploid cell proliferation assay and decreases RNA transcript abundance (PMID: 30209399). This variant has been detected in at least six individuals affected with breast and/or ovarian cancer (PMID: 32803532, 34120093, 34823292, 35087763, 35864222). 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. -
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Breast Center, Key Laboratory of Carcinogenesis and Translational Research