Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.2806_2809delGATA(p.Asp936SerfsTer63) 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]
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 17-43092721-TTATC-T is Pathogenic according to our data. Variant chr17-43092721-TTATC-T is described in ClinVar as [Pathogenic]. Clinvar id is 37491.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092721-TTATC-T is described in Lovd as [Pathogenic]. Variant chr17-43092721-TTATC-T is described in Lovd as [Pathogenic].
This variant deletes 4 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 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. -
Jan 16, 2018
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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Mar 04, 2025
Ambry Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The c.2806_2809delGATA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of 4 nucleotides at nucleotide positions 2806 to 2809, causing a translational frameshift with a predicted alternate stop codon (p.D936Sfs*63). This alteration has been reported in multiple individuals diagnosed with breast and/or ovarian cancer (Shattuck-Eidens D et al. JAMA 1997 Oct;278:1242-50; Rhei E et al. Cancer Res. 1998 Aug;58:3193-6; Weitzel JN et al Cancer Epidemiol. Biomarkers Prev. 2005 Jul;14:1666-71; Porchia, LM et al. J. Carcinogene. Mutagene. 2015 June;6:228; Villarreal-Garza C et al. Cancer 2015 Feb;121:372-8; Deng M et al. Int J Cancer, 2019 09;145:1517-1528). Of note, this alteration is also designated as 2925del4 in published literature. 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:3
Jan 01, 2025
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.Asp936Serfs*63) 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 and ovarian cancer (PMID: 9333265, 9699640, 22722201). This variant is also known as 2925del4. ClinVar contains an entry for this variant (Variation ID: 37491). For these reasons, this variant has been classified as Pathogenic. -
Apr 01, 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.2806_2809delGATA (p.Asp936SerfsX63) 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 (eg. (e.g. c.2864C>A, p.Ser955X; c.2868delT, p.Gln957fsX43; c.2934T>G, p.Tyr978X). The variant was absent in 245974 control chromosomes. c.2806_2809delGATA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer ( (Judkins 2005, Weitzel 2005, Vaca-Paniagua 2012, Rhei 1998, Shattuck-Eidens 1997,Villarreal-Garza 2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories and two expert panels (ENIGMA and CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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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not providedPathogenic:2
Oct 07, 2019
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; Observed in individuals with history consistent with pathogenic variants in this gene (Shattuck-Eidens 1997, Rhei 1998, Weitzel 2005, Vaca-Paniagua 2012, Villarreal-Garza 2015); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 31454914, 28127413, 25371446, 25236687, 16267036, 22655046, 22722201, 16030099, 9699640, 9333265, 30720863) -
Dec 27, 2019
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. In the published literature, this variant has been reported in individuals with hereditary breast and ovarian cancer (PMIDs: 9333265 (1997), 25236687 (2015), and 16030099 (2005)). Based on the available information, this variant is classified as pathogenic. -
Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group SPathogenic:1