Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.4945delA(p.Arg1649GlufsTer9) 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 (★★★). 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 17-43070968-CT-C is Pathogenic according to our data. Variant chr17-43070968-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 55328.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43070968-CT-C is described in Lovd as [Pathogenic]. Variant chr17-43070968-CT-C is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:3
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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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. -
Jun 21, 1999
Breast Cancer Information Core (BIC) (BRCA1)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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not provided Pathogenic:2
Jan 01, 2020
GeneKor MSA
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change deletes one nucleotide from exon 15 of the BRCA1 mRNA (c.4945delA), causing a frameshift after codon 1649 and the creation of a premature translation stop signal 9 amino acid residues later p.(Arg1649Glufs*9). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic. The mutation database ClinVar contains entries for this variant (Variation ID: 55328). -
Oct 26, 2023
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with personal and family history consistent with pathogenic variants in this gene (PMID: 10486320, 16287141, 23569316); Not observed in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 5064delA; This variant is associated with the following publications: (PMID: 10486320, 16287141, 23569316) -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant deletes 1 nucleotide in exon 15 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. This variant has been reported in an individual affected with prostate cancer and suspected hereditary breast and ovarian cancer families (PMID: 10486320, 23569316, 29446198, 31209999). 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. -
Mar 03, 2023
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.4945delA pathogenic mutation, located in coding exon 14 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 4945, causing a translational frameshift with a predicted alternate stop codon (p.R1649Efs*9). This alteration has been identified in multiple individuals diagnosed with hereditary breast and/or ovarian cancer syndrome (HBOC) (Gayther SA et al. Am J Hum Genet, 1999 Oct;65:1021-9; Kroiss R et al. Hum Mutat, 2005 Dec;26:583-9; Ramus SJ et al. Hum Mutat, 2007 Dec;28:1207-15). Of note, this alteration is also known as 5061delA in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -
Ovarian neoplasm Pathogenic:1
Dec 01, 2018
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research
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Hereditary breast ovarian cancer syndrome Pathogenic:1
Jan 31, 2014
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto