Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.1140dupG(p.Lys381GlufsTer3) 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]
BRCA1 Gene-Disease associations (from GenCC):
breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
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 17-43094390-T-TC is Pathogenic according to our data. Variant chr17-43094390-T-TC is described in ClinVar as Pathogenic. ClinVar VariationId is 231732.Status of the report is reviewed_by_expert_panel, 3 stars.
Breast-ovarian cancer, familial, susceptibility to, 1Pathogenic:3
Apr 01, 2023
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
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May 05, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
The pathogenic family mutation in the BRCA1 (c.1140_1141insG) was detected in this specimen. It is classified as pathogenic in ClinVar. This mutation creates stop codon 3 codons downstream. -
Dec 15, 2017
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
Jan 01, 2020
GeneKor MSA
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This sequence change inserts 1 nucleotide in exon 10 of the BRCA1 mRNA (c.1140dupG), causing a frameshift at codon 381. This creates a premature translational stop signal 3 amino acid residues later p.(Lys381Glufs*3) and is expected to result in an absent or disrupted protein product. The mutation database ClinVar contains entries for this variant (Variation ID: 231732). -
Jun 23, 2024
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 1259dup; This variant is associated with the following publications: (PMID: 30825404, 35216584, 35300142, 34930165, 30199306, 36385461, 28664506, 29297111, 27082205, 34980015, 34515413, 30322717, 31372034, 28888541, 31209999, 30352249, 35918668) -
BRCA1-related disorderPathogenic:1
Mar 19, 2024
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Loss-of-function variation in BRCA1 is an established mechanism of disease (PMID: 20301425). This is a recurrent Pathogenic variant that has been previously reported as a heterozygous change in patients with breast and/or ovarian cancer and is a considered a founder mutation in the Middle Eastern population (PMID: 27082205, 28664506, 29297111, 30825404). The c.1140dup (p.Lys381GlufsTer3) variant is absent from the gnomAD v4 population database and thus is presumed to be rare. Based on the available evidence, c.1140dup (p.Lys381GlufsTer3) is classified as Pathogenic. -
Familial cancer of breastPathogenic:1
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Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare
The c.1140dupG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of G at nucleotide position 1140, causing a translational frameshift with a predicted alternate stop codon (p.K381Efs*3). This alteration has been reported as a recurrent mutation in a cohort of Middle Eastern high-risk breast cancer patients and has been proposed as a Middle Eastern founder mutation (Bu R et al. Int. J. Cancer 2016 Apr; Alhuqail AJ et al. Breast Cancer Res. Treat. 2018 Jan). This mutation has also been detected in a Malaysian tirple-negative breast cancer proband (Yang XR et al. Breast Cancer Res. Treat. 2017 Oct;165(3):687-697). 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. -
Hereditary breast ovarian cancer syndromePathogenic:1
Jul 21, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This sequence change creates a premature translational stop signal (p.Lys381Glufs*3) 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 cancer and/or ovarian cancer (PMID: 27082205, 28664506, 29297111, 30825404). ClinVar contains an entry for this variant (Variation ID: 231732). For these reasons, this variant has been classified as Pathogenic. -