Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.3288_3289delAA(p.Leu1098SerfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,394 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 17-43092241-CTT-C is Pathogenic according to our data. Variant chr17-43092241-CTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 54821.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092241-CTT-C is described in Lovd as [Pathogenic]. Variant chr17-43092241-CTT-C is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:5
May 24, 2021
Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: case-control
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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. -
May 29, 2002
Breast Cancer Information Core (BIC) (BRCA1)
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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Mar 31, 2023
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Hereditary breast ovarian cancer syndrome Pathogenic:3
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
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Dec 23, 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.Leu1098Serfs*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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is also known as 3407delAA. ClinVar contains an entry for this variant (Variation ID: 54821). For these reasons, this variant has been classified as Pathogenic. -
Sep 15, 2016
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.3288_3289delAA (p.Leu1098Serfs) variant 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. If a protein product is made, it is predicted to truncate the highly conserved BRCT domain. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.3296delC/p.Pro1099fs). One in silico tool predicts a damaging outcome for this variant. This variant was absent in 121236 control chromosomes, but has been reported in multiple HBOC patients in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
not provided Pathogenic:2
Jan 01, 2020
GeneKor MSA
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant is a deletion of two nucleotides, resulting in a frameshift and the creation of a novel stop codon after 4 amino acid residues. It is expected to result in an absent or disrupted protein product. Truncating variants in the BRCA1 gene are known to be pathogenic. The mutation is also known as BRCA1 3407delAA. The mutation database Clinvar contains entries for this variant (Variation ID: 54821). -
Feb 02, 2018
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant deletes 2 nucleotides in exon 10 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 at least five individuals affected with breast cancer and/or ovarian cancer (PMID: 10866029, 15063971, 21324516, 26187060, 30287823). 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. -
Nov 25, 2024
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.3288_3289delAA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 3288 to 3289, causing a translational frameshift with a predicted alternate stop codon (p.L1098Sfs*4). This alteration has been identified in multiple individuals diagnosed with breast and/or ovarian cancer (Peyrat JP et al. Eur. J. Cancer Prev. 1998 Feb;7 Suppl 1:S7-12; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Momozawa Y et al. Nat Commun, 2018 10;9:4083; Wen WX et al. J Med Genet, 2018 02;55:97-103; Deng H et al. Mol Genet Genomic Med, 2019 06;7:e672; Zeng C et al. Breast Cancer Res Treat, 2020 Jun;181:465-473). Additionally, this alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Of note, this alteration is also designated as 3407delAA 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. -