Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.1292dupT(p.Leu431fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,198 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 17-43094238-T-TA is Pathogenic according to our data. Variant chr17-43094238-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 54188.Status of the report is reviewed_by_expert_panel, 3 stars.
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:4
Pathogenic, criteria provided, single submitter
clinical testing
Department of Medical Genetics, Oslo University Hospital
Jul 01, 2015
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Pathogenic, reviewed by expert panel
curation
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Sep 08, 2016
Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, criteria provided, single submitter
clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Oct 02, 2015
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Pathogenic, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
May 29, 2002
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not provided Pathogenic:3
Pathogenic, no assertion criteria provided
clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht
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Pathogenic, no assertion criteria provided
clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
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Pathogenic, no assertion criteria provided
clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
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Hereditary breast ovarian cancer syndrome Pathogenic:2
Pathogenic, no assertion criteria provided
research
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Jan 31, 2014
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Pathogenic, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Aug 11, 2023
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 54188). This variant is also known as 1409insT and 1411insT. This premature translational stop signal has been observed in individual(s) with breast cancer and pancreatic cancer (PMID: 7663517, 28900739, 29339979). This variant is present in population databases (rs80357528, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Leu431Phefs*5) 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). -
The c.1292dupT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of T at nucleotide position 1292, causing a translational frameshift with a predicted alternate stop codon (p.L431Ffs*5). This mutation has been reported in numerous individuals with hereditary breast and/or ovarian cancer, and has been reported as a common mutation in the Dutch population (Hogervorst FB et al. Nat. Genet., 1995 Jun;10:208-12; Janaviius R. EPMA J, 2010 Sep;1:397-412; Vos JR et al. Cancer Epidemiol. Biomarkers Prev., 2014 Nov;23:2482-91; Karami F et al. Biomed Res Int, 2013 Nov;2013:928562; Papelard H et al. Br. J. Cancer, 2000 Sep;83:719-24). Of note, this alteration is also designated as 1411insT and 1409insT 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. -