Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.5106delA(p.Lys1702AsnfsTer4) 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. K1702K) 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]
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 17-43063919-AT-A is Pathogenic according to our data. Variant chr17-43063919-AT-A is described in ClinVar as [Pathogenic]. Clinvar id is 55402.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43063919-AT-A is described in Lovd as [Pathogenic]. Variant chr17-43063919-AT-A is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1Pathogenic:3
May 29, 2002
Breast Cancer Information Core (BIC) (BRCA1)
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
- -
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
- -
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. -
not providedPathogenic:2
Jul 26, 2022
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; Not observed at significant frequency 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 5225del; This variant is associated with the following publications: (PMID: 11938448, 32341426, 17148771, 32438681, 31853058) -
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
NVA pending - needed. This is the type of variant expected to cause the disorder. See case BB5454 for familial report -
Hereditary breast ovarian cancer syndromePathogenic:2
Sep 01, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This premature translational stop signal has been observed in individual(s) with breast/ovarian cancer (PMID: 11938448, 17148771). This variant is also known as 5225delA. ClinVar contains an entry for this variant (Variation ID: 55402). For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys1702Asnfs*4) 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). -
Jan 31, 2014
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:research
- -
Breast and/or ovarian cancerPathogenic:1
Sep 16, 2015
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
- -
BRCA1-related cancer predispositionPathogenic:1
Jun 27, 2024
All of Us Research Program, National Institutes of Health
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This variant deletes 1 nucleotide in exon 17 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 ovarian cancer and two families affected with breast and/or ovarian cancer (PMID: 11938448, 17148771, 32438681). 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. -
The c.5106delA pathogenic mutation (also known as 5225delA), located in coding exon 16 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 5106, causing a translational frameshift with a predicted alternate stop codon. This mutation has been identified in an Italian breast/ovarian cancer family (Nedelcu R, Eur. J. Hum. Genet. 2002 Feb; 10(2):150-2). In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -