ClinVar Genomic variation as it relates to human health

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

Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Konstantopoulou et al., 2014; Sun et al., 2017; Mathias et al., 2019; Wang et al., 2019; De Talhouet et al., 2020); Nonsense 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 8592G>A; This variant is associated with the following publications: (PMID: 18489799, 24010542, 28724667, 31432501, 30968603, 32341426, 29084914, 26028024, 31209999, 24156927, 23772696, 26300996, 22762150, 31825140, 30702160, 29446198)

Variant summary: BRCA2 c.8364G>A (p.Trp2788X) 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 251424 control chromosomes. c.8364G>A has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The p.W2788* pathogenic mutation (also known as c.8364G>A), located in coding exon 18 of the BRCA2 gene, results from a G to A substitution at nucleotide position 8364. This changes the amino acid from a tryptophan to a stop codon within coding exon 18. This mutation has been detected in multiple individuals with breast and/or ovarian cancer (Thomassen et al. Acta Oncol 2008;47(4):772-7; Lecarpentier J et al. Breast Cancer Res. 2012 Jul;14:R99; Sun et al. Clin. Cancer Res. 2017 Oct;23(20):6113-6119; Labidi-Galy et al. Clin. Cancer Res. 2018 01;24(2):326-333; Rebbeck et al. Hum. Mutat. 2018 05;39(5):593-620; Bhaskaran et al. Int. J. Cancer 2019 Aug;145(4):962-973; Fostira et al. J. Med. Genet. 2019 Jul; Wang et al. Mol Genet Genomic Med 2019 Jun;7(6):e677). Of note, this alteration is also designated as 8592G>A 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.

This sequence change creates a premature translational stop signal (p.Trp2788*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 52566). For these reasons, this variant has been classified as Pathogenic.

This BRCA2 nonsense variant has been reported in multiple individuals affected with hereditary breast and ovarian cancer. It results in a premature stop codon in exon 19 likely leading to nonsense-mediated decay and lack of protein production. This variant is absent from a large population database and has an entry in ClinVar. We consider c.8364G>A to be pathogenic.

This variant changes 1 nucleotide in exon 19/27 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been detected in at least 11 individuals affected with breast or ovarian cancer (PMID: 24010542, 26028024) and over 40 suspected hereditary breast and ovarian cancer families (PMID: 29446198). This variant alsohas been reported in a multifactorial analysis with a likelihood ratio for pathogenicity based on personal and family history of 0.975 from log(LR)=-0.011170717 for two carriers (PMID: 31853058). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

The BRCA2 c.8364G>A variant is predicted to result in premature protein termination (p.Trp2788*). This variant was reported in individuals with breast and/or ovarian cancer (Table S3, Sun et al. 2017. PubMed ID: 28724667; Table S3, Labidi-Galy et al. 2018. PubMed ID: 29084914; Table S1, De Talhouet et al. 2020. PubMed ID: 32341426). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/52566/). Nonsense variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic.