Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000357654.9(BRCA1):c.2486_2487del(p.Phe829Ter) 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. F829F) 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 17-43093043-TAA-T is Pathogenic according to our data. Variant chr17-43093043-TAA-T is described in ClinVar as [Pathogenic]. Clinvar id is 54583.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43093043-TAA-T is described in Lovd as [Pathogenic].
This variant deletes 2 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least four individuals affected with breast and ovarian cancer (PMID: 16616110, 20859677, 30103829; Color internal data). 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. -
Pathogenic, criteria provided, single submitter
clinical testing
Ambry Genetics
Sep 01, 2021
The c.2486_2487delTT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 2486 to 2487, causing a translational frameshift with a predicted alternate stop codon (p.F829*). This alteration has been reported in multiple Chilean breast and/or ovarian cancer families (Jara L et al. Cancer Genet. Cytogenet., 2006 Apr;166:36-45; Gonzalez-Hormazabal P et al. Breast Cancer Res. Treat., 2011 Apr;126:705-16; Alvarez C et al. Oncotarget, 2017 Sep;8:74233-74243; Cardoso FC et al. Hum Genomics, 2018 08;12:39). 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. -
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1
Pathogenic, reviewed by expert panel
curation
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Dec 15, 2017
Variant allele predicted to encode a truncated non-functional protein. -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund
Oct 05, 2022
- -
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Dec 17, 2023
This sequence change creates a premature translational stop signal (p.Phe829*) 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 epithelial ovarian cancer (PMID: 30103829). ClinVar contains an entry for this variant (Variation ID: 54583). For these reasons, this variant has been classified as Pathogenic. -
Familial cancer of breast Other:1
not provided, no classification provided
literature only
ClinVar Staff, National Center for Biotechnology Information (NCBI)