ClinVar Genomic variation as it relates to human health

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

The BRCA2 c.7878G>A variant is predicted to result in premature protein termination (p.Trp2626*). This variant has been reported in several individuals with a personal and/or family history of breast and/or ovarian cancer (see for example, Lilyquist J et al 2017. PubMed ID: 28888541; Kwong A et al 2015. PubMed ID: 26187060; Couch FJ et al 2014. PubMed ID: 25452441; Carney ME et al 2010. PubMed ID: 21218378; Kwong A et al 2012. PubMed ID: 22970155). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare in the general population. Nonsense variants in BRCA2 are expected to be pathogenic. This variant is classified as pathogenic by several submitters in ClinVar, including by an expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/38124/). This variant is interpreted as pathogenic.

The p.W2626* pathogenic mutation (also known as c.7878G>A) located in coding exon 16 of the BRCA2 gene, results from a G to A substitution at nucleotide position 7878. This changes the amino acid from a tryptophan to a stop codon within coding exon 16. This alteration has been reported in multiple high-risk breast and/or ovarian cancer patients in the literature (Carney ME et al. Hawaii Med J. 2010 Nov;69:268-71; Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11; Kwong A et al. PLoS ONE. 2012 Sep;7:e43994; Kwong A et al. J. Med. Genet. 2016 Jan;53:15-23; Rebbeck TR et al. Hum Mutat. 2018 May;39(5):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.

This variant changes 1 nucleotide in exon 17 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 10 individuals affected with breast cancer (PMID: 21218378, 25452441, 26187060, 33471991; Color internal data; Leiden Open Variation Database DB-ID BRCA2_005264) and one proband who also had cancer of the brain (PMID: 21218378). 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.

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; Reported in individuals with personal or family history of breast and/or ovarian cancer (Carney et al., 2010; Kwong et al., 2012; Couch et al., 2015; Ow et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 30093976, 29487695, 29937436, 28888541, 21702907, 21218378, 26187060, 27157322, 22970155, 25452441, 32467295, 30702160, 29446198, 30787465, 33858678, 34022715, 25085752, 32091409, Huang_2021_Case Report, 30875412, 31825140)

Variant summary: BRCA2 c.7878G>A (p.Trp2626X) 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. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251276 control chromosomes. c.7878G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Carney_2010, Kwong_2012, Couch_2015, Hondow_2011). 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. The following publications have been ascertained in the context of this evaluation (PMID: 21702907, 21218378, 22970155, 25452441). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change creates a premature translational stop signal (p.Trp2626*) 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 hereditary breast and ovarian cancer (PMID: 21218378, 22970155, 25452441, 26187060). This variant is also known as 8106G>A. ClinVar contains an entry for this variant (Variation ID: 38124). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

The BRCA2 p.Trp2626X variant was identified in 6 of 1438 proband chromosomes (frequency: 0.004) from multiethnic Asian individuals or families with high risk breast cancer; the variant being frequent in the Hong Kong population (Kwong 2012, Kwong 2015). The variant was also identified in dbSNP (ID: rs80359013) “With Pathogenic” allele, ClinVar (classified as pathogenic, reviewed by expert panel; submitters: ENIGMA, Counsyl, Invitae, Ambry Genetics, GeneDx, SCRP and CIMBA), Clinvitae (4x), BIC Database (1x, with unknown clinical importance, class 3-uncertain significance), and ARUP Laboratories (5-definitely pathogenic). The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, LOVD 3.0, UMD-LSDB, Zhejiang Colon Cancer Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The variant was also identified by our laboratory in 3 individuals at risk of familial breast cancer. The p.Trp2626X variant leads to a premature stop codon at position 2626, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.