Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.4391delC(p.Pro1464LeufsTer2) 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 17-43076580-AG-A is Pathogenic according to our data. Variant chr17-43076580-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 37589.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43076580-AG-A is described in Lovd as [Pathogenic]. Variant chr17-43076580-AG-A is described in Lovd as [Pathogenic]. Variant chr17-43076580-AG-A is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:5
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. -
Dec 23, 2003
Breast Cancer Information Core (BIC) (BRCA1)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Mar 02, 2020
BRCAlab, Lund University
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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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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Aug 18, 2009
Sharing Clinical Reports Project (SCRP)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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not provided Pathogenic:2
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Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
The BRCA1 p.Pro1464LeufsX2 variant was identified in 1 of 106 proband chromosomes (frequency: 0.009) from individuals or families with breast and ovarian cancer of Turkish ethnicity (Yazici 2000). The variant was also identified in dbSNP (ID: rs80357916) as with pathogenic allele: in the ClinVar and Clinvitae databases as pathogenic by ENIGMA, Consortium of Investigators of Modifiers of BRCA1/2, Sharing Clinical Reports Project and Breast Cancer Information Core. The variant was further identified in LOVD 3.0 database 2X with variant allele predicted to encode truncated non-functional protein; in UMD-LSDB database 15X with biological significance and a classification of class 5; in BIC Database 1X with clinical importance, class 5; and in ARUP Laboratories as definitely pathogenic. The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, Zhejiang Colon Cancer Database, databases. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, and the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.4391del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1464 and leads to a premature stop codon at position 1465. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -
Apr 16, 2020
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data. -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.4391delC pathogenic mutation, located in coding exon 12 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 4391, causing a translational frameshift with a predicted alternate stop codon (p.P1464Lfs*2). This mutation has been reported in individuals with breast cancer, triple negative breast cancer and fallopian tube cancer (Yazici H et al. Br. J. Cancer 2000 Sep;83:737-42; Laki F et al. Cancer 2007 May;109:1784-90; Vincent-Salomon A et al. Cancer Res. 2007 Jun;67:5134-40; Davies H et al. Nat. Med. 2017 Apr;23:517-525). Of note, this alteration is also designated as 4508delC and c.4389delC in 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. -
Feb 12, 2020
Color Diagnostics, LLC DBA Color Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant deletes 1 nucleotide in exon 13 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. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 15887246). 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. -
Hereditary breast ovarian cancer syndrome Pathogenic:1
Jul 10, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with personal and family history of breast and/or ovarian cancer (PMID: 10952777, 31954625, 32341426). This variant is also known as 4508delC. ClinVar contains an entry for this variant (Variation ID: 37589). For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Pro1464Leufs*2) 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). -