Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.3761_3762insTT(p.Lys1254AsnfsTer2) 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 17-43091769-C-CAA is Pathogenic according to our data. Variant chr17-43091769-C-CAA is described in ClinVar as [Pathogenic]. Clinvar id is 91614.Status of the report is reviewed_by_expert_panel, 3 stars.
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:6
Pathogenic, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Apr 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, no assertion criteria provided
clinical testing
Sharing Clinical Reports Project (SCRP)
May 01, 2012
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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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Pathogenic, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
Jan 08, 2024
This variant inserts 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. To our knowledge, this variant has not been reported in individuals affected with BRCA1-related disorders in the literature. 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:2
Pathogenic, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Feb 28, 2023
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 91614). This sequence change creates a premature translational stop signal (p.Lys1254Asnfs*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). 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/or family history of breast and/or ovarian cancer (PMID: 29446198). This variant is also known as 3880insTT. -
Pathogenic, no assertion criteria provided
research
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
The c.3761_3762insTT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from an insertion of two nucleotides at position 3761, causing a translational frameshift with a predicted alternate stop codon (p.K1254Nfs*2). 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. -