Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.134+2T>C variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as 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]
BRCA1 Gene-Disease associations (from GenCC):
breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Our verdict: Pathogenic. The variant received 12 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.009656653 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43115724-A-G is Pathogenic according to our data. Variant chr17-43115724-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 91547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Breast-ovarian cancer, familial, susceptibility to, 1Pathogenic:5
Nov 01, 2007
Sharing Clinical Reports Project (SCRP)
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
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Mar 16, 2023
Baylor Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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May 05, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
A splice-site mutation in intervening segment 3 was detected in this patient. This mutation is reported in ClinVar and other databases as pathogenic. -
Oct 02, 2015
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
This variant causes a T to C nucleotide substitution at the +2 position of intron 3 of the BRCA1 gene. This variant is also known as IVS3+2T>C based on Breast Cancer Information Core (BIC) nomenclature. 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 to be loss-of-function in a haploid cell proliferation assay (PMID: 30209399). This variant has been detected in two individuals affected with breast cancer (PMID: 35886069; Color internal data). Different variants affecting the same splice donor site, c.134+2T>G, c.134+1G>T, c.134+1G>A and c.134+1G>C, are known to be disease-causing (ClinVar variation ID: 54210, 54209, 267499, 125563). This variant creates an alternative donor site beginning with a GC dinucleotide. Some GC variant donor sites have been shown to generate variable levels of wild-type transcript (PMID: 31131953). Hence, this variant could be less penetrant than a conventional splice donor site loss variant. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Aug 28, 2023
Ambry Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The c.134+2T>C intronic pathogenic mutation results from a T to C substitution two nucleotides after coding exon 2 in the BRCA1 gene. This nucleotide position is highly conserved in available vertebrate species. This alteration has been reported in the literature in individuals with suspected hereditary breast and ovarian cancer (Li A et al. Gynecol Oncol, 2018 10;151:145-152, Guacci A et al. J Clin Lab Anal, 2018 Jul;32:e22418, Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620, Santonocito C et al. Cancers (Basel), 2020 May;12:). 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 silico splice site analysis predicts that this alteration will weaken the native splice donor site; however direct evidence is insufficient (Ambry internal data). In addition to the clinical data presented in the literature, 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 a disease-causing mutation. -
not providedPathogenic:1
Dec 15, 2023
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The BRCA1 c.134+2T>C variant disrupts a canonical splice-donor site and interferes with normal BRCA1 mRNA splicing. This variant has been reported in the published literature in individuals affected with breast and/or ovarian cancer (PMIDs: 32438681 (2020), 30209399 (2018), 30078507 (2018), 29484706 (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 pathogenic. -
Hereditary breast ovarian cancer syndromePathogenic:1
Feb 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This sequence change affects a donor splice site in intron 3 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 29484706, 30078507). ClinVar contains an entry for this variant (Variation ID: 91547). 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 disruption of this splice site affects BRCA1 function (PMID: 30209399). Studies have shown that disruption of this splice site results in skipping of exon 3, and produces a non-functional protein and/or introduces a premature termination codon (internal data). For these reasons, this variant has been classified as Pathogenic. -