ClinVar Genomic variation as it relates to human health

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

This nonsense variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals and families affected breast or ovarian cancer in the published literature (PMID: 29446198 (2018), 24249303 (2015), 9609997 (1998)). Therefore, the variant is classified as pathogenic and this individual is at increased risk of developing BRCA2 related cancers.

This variant changes 1 nucleotide in exon 21 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 reported in 1 individual affected with pancreatic cancer and 1 individual affected with breast cancer (PMID: 27271530, 31469826, 32816949). This variant has been reported in at least 1 family with multiple individuals affected with breast cancer (PMID: 24249303, 19806429, 9609997) and has been identified in 3 families among the CIMBA participants (PMID: 29446198). 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.

This variant is denoted BRCA2 c.8677C>T at the cDNA level and p.Gln2893Ter (Q2893X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also known as BRCA2 8905C>T using alternate nomenclature, has been reported in association with Hereditary Breast and Ovarian Cancer syndrome (Katagiri 1998, Laitman 2011, Takahashi 2017) and is considered pathogenic.

Variant summary: BRCA2 c.8677C>T (p.Gln2893X) 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 251318 control chromosomes. c.8677C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Katagiri_1998, Laitman_2011, Nakamura_2013, Nomizu_2012). 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. Multiple clinical diagnostic laboratories and an expert panel (ENIGMA) 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.

The stop gained c.8677C>T (p.Gln2893Ter) variant in BRCA2 gene has been previously reported in multiple individuals affected with Breast Cancer (Katagiri T, et al., 1998; Nomizu T, et al., 2012; Nakamura et al., 2015). The p.Gln2893Ter variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). The nucleotide change c.8677C>T in BRCA2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This sequence change creates a premature translational stop signal (p.Gln2893Ter) in the BRCA2 gene. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in BRCA2 gene have been previously reported to be pathogenic (Borg et al., 2010). For these reasons, this variant has been classified as Pathogenic.

This sequence change creates a premature translational stop signal (p.Gln2893*) 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 premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 9609997, 26187060). ClinVar contains an entry for this variant (Variation ID: 38177). For these reasons, this variant has been classified as Pathogenic.

This variant changes 1 nucleotide in exon 21 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 reported in 1 individual affected with pancreatic cancer and 1 individual affected with breast cancer (PMID: 27271530, 31469826, 32816949). This variant has been reported in at least 1 family with multiple individuals affected with breast cancer (PMID: 24249303, 19806429, 9609997) and has been identified in 3 families among the CIMBA participants (PMID: 29446198). 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 p.Q2893* variant (also known as c.8677C>T), located in coding exon 20 of the BRCA2 gene, results from a C to T substitution at nucleotide position 8677. This changes the amino acid from a glutamine to a stop codon within coding exon 20. This mutation (designated as "Gln 2893 ter") was reported in a family from Japan with hereditary breast cancer (Katagiri T et al. J. Hum. Genet. 1998;43:42-8). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). 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.