Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.89T>A(p.Leu30Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. L30L) has been classified as Uncertain significance.
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 18 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 3461 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43115771-A-T is Pathogenic according to our data. Variant chr17-43115771-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 55745.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43115771-A-T is described in Lovd as [Pathogenic]. Variant chr17-43115771-A-T 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
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Pathogenic, reviewed by expert panel
curation
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Oct 18, 2016
Variant allele predicted to encode a truncated non-functional protein. -
not provided, no classification provided
in vitro
Brotman Baty Institute, University of Washington
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not provided Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Feb 06, 2023
This nonsense variant causes the premature termination of BRCA1 protein synthesis. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an individual with breast cancer (PMID: 18159056 (2007)). Functional studies for this variant demonstrate reduced BRCA1-BARD1 binding (PMID: 25823446 (2015)), reduced E3 ubiquitin ligase activity (PMID: 25823446 (2015)), and reduced cell viability in a homology-directed DNA repair (HDR) assay (PMID: 30209399 (2018)). Based on the available information, this variant is classified as pathogenic. -
The p.L30* pathogenic mutation (also known as c.89T>A), located in coding exon 2 of the BRCA1 gene, results from a T to A substitution at nucleotide position 89. This changes the amino acid from a leucine to a stop codon within coding exon 2. This mutation (designated as L30X) was observed in a Hispanic individual from a cohort of multi-ethnic female breast cancer patients in the US (John EM et al. JAMA 2007 Dec;298:2869-76). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Invitae
Nov 11, 2023
This sequence change creates a premature translational stop signal (p.Leu30*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 18159056). ClinVar contains an entry for this variant (Variation ID: 55745). For these reasons, this variant has been classified as Pathogenic. -