ClinVar Genomic variation as it relates to human health

Variant allele predicted to encode a truncated non-functional protein.

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.

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)

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.

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.

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.

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.