Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.4533_4534delCA(p.His1511GlnfsTer9) 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 17-43074471-CTG-C is Pathogenic according to our data. Variant chr17-43074471-CTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 55223.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43074471-CTG-C is described in Lovd as [Pathogenic]. Variant chr17-43074471-CTG-C is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:5
Feb 22, 2018
Institute of Human Genetics, University of Leipzig Medical Center
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. -
Feb 26, 2016
Counsyl
Significance: Pathogenic
Review Status: criteria provided, single submitter
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
- -
May 29, 2002
Breast Cancer Information Core (BIC) (BRCA1)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
- -
not provided Pathogenic:2
Nov 03, 2021
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Apr 21, 2022
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Hereditary breast ovarian cancer syndrome Pathogenic:2
Dec 22, 2017
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: The BRCA1 c.4533_4534delCA (p.His1511GlnfsX9) variant (also known as 4650delCA and 4652delCA) results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Glu1694X, p.Gln1747X, p.Arg1835X, etc.). This variant is absent in 277114 control chromosomes (gnomAD). This variant has been reported in at least four unrelated HBOC patients in literature (Meisel_2017, Judkins_2005, Meindl_2002, Meindl_2000). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Dec 04, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
ClinVar contains an entry for this variant (Variation ID: 55223). For these reasons, this variant has been classified as Pathogenic. This variant is also known as 4652delCA (1519X). This sequence change creates a premature translational stop signal (p.His1511Glnfs*9) 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 breast and/or ovarian cancer (PMID: 11802209). -
BRCA1-related cancer predisposition Pathogenic:1
Sep 16, 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 2 nucleotides in exon 14 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 three individuals affected with breast cancer (PMID: 28145423, 29791287), over 10 suspected hereditary breast and ovarian cancer families (PMID: 10699917, 11802209, 28324225, 29446198) and in one individual unaffected with cancer (PMID: 31395037). 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. -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.4533_4534delCA pathogenic mutation, located in coding exon 13 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 4533 to 4534, causing a translational frameshift with a predicted alternate stop codon (p.H1511Qfs*9). This alteration has been seen in multiple HBOC German families (Meindl A et al. Int. J. Cancer. 2002 Feb;97:472-80; Meisel C et al. Arch. Gynecol. Obstet., 2017 May;295:1227-1238). Of note, this variant may be referred to as 4652delCA in some 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