Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.134+2T>C variant causes a splice donor 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]
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.009477826 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 id is 91547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43115724-A-G is described in Lovd as [Pathogenic]. Variant chr17-43115724-A-G is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:6Other:1
Pathogenic, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Dec 26, 2015
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Pathogenic, no assertion criteria provided
clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center
May 05, 2023
A splice-site mutation in intervening segment 3 was detected in this patient. This mutation is reported in ClinVar and other databases as pathogenic. -
Pathogenic, no assertion criteria provided
clinical testing
Sharing Clinical Reports Project (SCRP)
Nov 01, 2007
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Pathogenic, criteria provided, single submitter
clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
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. -
Pathogenic, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Jan 09, 2024
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). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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). Based on the available evidence, this variant is classified as Pathogenic. -
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Apr 11, 2023
Experimental studies have shown that disruption of this splice site affects BRCA1 function (PMID: 30209399). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 3 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 91547). Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 29484706, 30078507). This variant is not present in population databases (gnomAD no frequency). 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 disrupted protein product. -