Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.3767_3768delCA(p.Thr1256ArgfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,878 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 17-43091762-CTG-C is Pathogenic according to our data. Variant chr17-43091762-CTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 182074.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43091762-CTG-C is described in Lovd as [Pathogenic]. Variant chr17-43091762-CTG-C is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:4
Mar 02, 2020
BRCAlab, Lund University
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Mar 28, 2023
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
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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Apr 22, 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. -
Hereditary breast ovarian cancer syndrome Pathogenic:3
Jun 03, 2019
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: BRCA1 c.3767_3768delCA (p.Thr1256ArgfsX10) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant was absent in 251226 control chromosomes. c.3767_3768delCA has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Andres_2014, Whitworth_2015, Kwong_2016, Mafficini_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Jan 13, 2017
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The p.Thr1256fs variant in BRCA1 has been reported in 1 individual with breast c ancer (Andres 2014) and was absent from large population studies. This variant i s predicted to cause a frameshift, which alters the protein?s amino acid sequenc e beginning at position 1256 and leads to a premature termination codon 10 amino acids downstream. This alteration is then predicted to lead to a truncated or a bsent protein. Heterozygous loss of function of function of the BRCA1 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). I n addition, this variant was classified as Pathogenic on April 22, 2016 by the C linGen-approved ENIGMA expert panel (ClinVar SCV000282318.1). In summary, the p. Thr1256fs variant meets criteria to be classified as pathogenic for HBOC in an a utosomal dominant manner. -
Aug 12, 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.Thr1256Argfs*10) 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 BRCA1-related conditions (PMID: 23982851, 27157322). This variant is also known as "3886 of CA; stop1264". ClinVar contains an entry for this variant (Variation ID: 182074). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:2
Jan 30, 2025
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); Observed in association with hereditary breast and/or ovarian cancer (PMID: 23982851, 26187060, 27157322, 31742824); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 3886delCA; This variant is associated with the following publications: (PMID: 23982851, 27157322, 26315209, 26187060, 25248401, 26745875, 30702160, 31742824, 31825140) -
Aug 17, 2018
Clinical Genetics and Genomics, Karolinska University Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.3767_3768delCA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at positions 3767 and 3768, causing a translational frameshift with a predicted alternate stop codon (p.T1256Rfs*10). This pathogenic mutation (also designated as 'del CA at position 3886') has been identified in multiple high-risk breast/ovarian cancer families (Andrés R et al. Clin Transl Oncol 2014 Mar; 16(3):280-4; Mafficini A et al. Oncotarget 2016 Jan; 7(2):1076-83; Kwong A et al. J Med Genet, 2016 Jan;53:15-23; Shao D et al. Cancer Sci, 2020 Feb;111:647-657; Gao X et al. Hum Mutat, 2020 03;41:696-708). 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. -