Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.1439dupA(p.Asn480LysfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. N480N) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
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 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43094091-A-AT is Pathogenic according to our data. Variant chr17-43094091-A-AT is described in ClinVar as Pathogenic. ClinVar VariationId is 54252.Status of the report is reviewed_by_expert_panel, 3 stars.
Breast-ovarian cancer, familial, susceptibility to, 1Pathogenic:5
Feb 20, 2004
Breast Cancer Information Core (BIC) (BRCA1)
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
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Sep 08, 2016
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Significance:Pathogenic
Review Status:reviewed by expert panel
Collection Method:curation
Variant allele predicted to encode a truncated non-functional protein. -
Oct 02, 2015
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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Mar 13, 2022
Baylor Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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May 01, 2012
Sharing Clinical Reports Project (SCRP)
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
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Hereditary breast ovarian cancer syndromePathogenic:3
Apr 20, 2017
Department of Pathology and Molecular Medicine, Queen's University
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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May 26, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This sequence change creates a premature translational stop signal (p.Asn480Lysfs*10) 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: 10528853). ClinVar contains an entry for this variant (Variation ID: 54252). For these reasons, this variant has been classified as Pathogenic. -
Apr 16, 2014
Department of Pathology and Laboratory Medicine, Sinai Health System
The c.1439dupA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of A at nucleotide position 1439, causing a translational frameshift with a predicted alternate stop codon (p.N480Kfs*10). This mutation has been reported in multiple individuals diagnosed with hereditary breast and/or ovarian cancer (van Orsouw NJ et al. J Med Genet. 1999 Oct;36(10):747-53; Bayraktar S et al. Cancer 2012 Mar;118(6):1515-22; Zhang J et al. Breast Cancer Res. Treat. 2016 Aug;158(3):455-62; Sun J et al. Clin Cancer Res, 2017 Oct;23:6113-6119; Li A et al. Gynecol Oncol, 2018 10;151:145-152; Liang Y et al. Med Sci Monit, 2018 Apr;24:2465-2475). Of note, this mutation is also designated as 1558insA in published 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. -
Feb 16, 2023
Color Diagnostics, LLC DBA Color Health
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This variant inserts 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 1558insA and c.1439_1440insA in the literature. This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 27393621, 29681614, 30078507). 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 Pathogenic. -
Breast and/or ovarian cancerPathogenic:1
Aug 10, 2021
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario