Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_007294.4(BRCA1):c.134+3A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,994 control chromosomes in the GnomAD database, with no homozygous occurrence. 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
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 17-43115723-T-A is Pathogenic according to our data. Variant chr17-43115723-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 531302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1Other:1
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Brotman Baty Institute, University of Washington
Significance: not provided
Review Status: no classification provided
Collection Method: in vitro
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Aug 03, 2022
Baylor Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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not provided Pathogenic:1
May 08, 2024
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The BRCA1 c.134+3A>T variant has been reported in an RNA study to cause skipping of exon 3 and the creation of a premature termination codon in the affected transcript (PMID: 32123317 (2020)). A saturation genome editing assay measuring DNA repair-dependent cell survival classified this variant as non-functional (PMID: 30209399 (2018)). To the best of our knowledge, this variant has not been reported in individuals with BRCA1-related conditions in the published literature. However, a different variant at the same nucleotide, BRCA1 c.134+3A>C (also known as IVS3+3A>C), has been observed in a hereditary breast/ovarian cancer family and shown to cause aberrant splicing as well (PMID: 12759930 (2003)). The BRCA1 c.134+3A>T 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. -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.134+3A>T intronic pathogenic mutation results from an A to T substitution 3 nucleotides after coding exon 2 in the BRCA1 gene. 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. This alteration results in skipping of coding exon 2 (also known as exon 3 in the literature) resulting in a transcript with a premature termination codon (Wai HA et al. Genet Med, 2020 06;22:1005-1014). 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). In addition, several variants at the same donor site, including BRCA1 c.134+5G>A and BRCA1 c.134+5G>T, cause the same splice defect (Ambry internal data; Baert A et al. Hum. Mutat., 2018 04;39:515-526). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Hereditary breast ovarian cancer syndrome Pathogenic:1
Nov 10, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change falls in intron 3 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. 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: 531302). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects BRCA1 function (PMID: 30209399). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 3, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 32123317; internal data). This variant disrupts the c.134+3A nucleotide in the BRCA1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 12402332, 12759930). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -