Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000357654.9(BRCA1):c.4745del(p.Asp1582AlafsTer19) 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. D1582D) 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]
Verdict is Pathogenic. Variant got 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 17-43071168-GT-G is Pathogenic according to our data. Variant chr17-43071168-GT-G is described in ClinVar as [Pathogenic]. Clinvar id is 55278.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43071168-GT-G is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:4
Pathogenic, reviewed by expert panel
curation
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Sep 08, 2016
Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, no assertion criteria provided
clinical testing
BRCAlab, Lund University
Aug 26, 2022
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Pathogenic, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
Jun 21, 1999
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Pathogenic, criteria provided, single submitter
clinical testing
Department of Medical Genetics, Oslo University Hospital
Jul 01, 2015
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Hereditary breast ovarian cancer syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Aug 11, 2022
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 55278). This variant is also known as 4864delA. This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 17574839). This variant is present in population databases (rs80357907, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Asp1582Alafs*19) 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). -
Pathogenic, criteria provided, single submitter
clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Jul 15, 2021
The p.Asp1582AlafsX19 variant in BRCA1 has been reported in >20 individuals with breast and ovarian cancer (HBOC; Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/bic/, Oslo University Hospital: ClinVar SCV000564331.1) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1582 and leads to a premature termination codon 19 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism for HBOC. Additionally, this variant was classified as pathogenic on Sep 08, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000300157.2). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP criteria applied: PVS1, PS4, PM2_Supporting. -
Pathogenic, no assertion criteria provided
research
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
The c.4745delA pathogenic mutation, located in coding exon 14 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 4745, causing a translational frameshift with a predicted alternate stop codon (p.D1582Afs*19). In one study, this alteration was observed in 42 individuals from 6 Norwegian families undergoing testing given a personal and/or family history of HBOC-related cancers (Møller P et al. Eur J Cancer, 2007 Jul;43:1713-7). Of note, this alteration is also designated as 4864delA in the published literature. 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. -