ClinVar Genomic variation as it relates to human health

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

Variant summary: BRCA2 c.7757G>A (p.Trp2586X) 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 allele was found at a frequency of 8e-06 in 251434 control chromosomes. c.7757G>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 large consortium (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.

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; Observed in individuals with personal or family history of BRCA2-related cancers (Perkowska et al., 2003; Jonsson et al., 2005; George et al., 2013; Walker et al., 2014; Murali et al., 2021; Evans et al., 2022); 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 7985G>A; This variant is associated with the following publications: (PMID: 25628955, 25371446, 26833046, 28127413, 11802209, 19620486, 34657373, 29922827, 28888541, 23633455, 12673801, 23035815, 24333842, 16140926, 16528604, 27225637, 25485004, 12442275, 22655046, 25716084, 23233716, 27836010, 19899408, 17761984, 22711857, 29752822, 29446198, 30720243, 25525159, 31825140, 30787465, 33087929, 23524863, 20104584, 23569316, 33113089, 34399810, 33471991, 33758026)

This sequence change creates a premature translational stop signal (p.Trp2586*) 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 present in population databases (rs80359003, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer and prostate cancer (PMID: 11802209, 12673801, 16528604, 23035815, 23569316, 23633455, 25485004). ClinVar contains an entry for this variant (Variation ID: 52401). For these reasons, this variant has been classified as Pathogenic.

The p.W2586* pathogenic mutation (also known as c.7757G>A), located in coding exon 15 of the BRCA2 gene, results from a G to A substitution at nucleotide position 7757. This changes the amino acid from a tryptophan to a stop codon within coding exon 15. This alteration has been reported in multiple breast and/or ovarian cancer families (Perkowska M et al. Hum. Mutat., 2003 May;21:553-4; Jönsson G et al. Cancer Res., 2005 Sep;65:7612-21; Alsop K et al. J Clin Oncol, 2012 Jul;30:2654-63; Conner JR et al. Gynecol. Oncol., 2014 Feb;132:280-6; Walker R et al. Can Urol Assoc J, 2014 Nov;8:E783-8; Li JY et al. Int J Cancer, 2019 01;144:281-289; Petridis C et al. Cancer Epidemiol Biomarkers Prev, 2019 07;28:1162-1168; Lattimore V et al. Breast Cancer Res Treat, 2021 Feb;185:583-590; Dorling et al. N Engl J Med. 2021 02;384:428-439). This mutation has also been reported in individuals diagnosed with prostate cancer (Willems-Jones A et al. BJU Int. 2012 Dec;110(11 Pt C):E1181-6; Sandhu SK et al. Ann Oncol, 2013 May;24:1416-8; Walker R et al. Can Urol Assoc J 2014 Nov; 8(11-12):E783-8). This mutation has been identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). Of note, this alteration is also designated as 7985G>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.

The BRCA2 c.7757G>A variant is classified as Pathogenic (PVS1, PM2, PP5) The BRCA2 c.7757G>A variant is a single nucleotide change which is predicted to result in premature termination of the protein product at codon 2586. The variant is rare in population databases (gnomAD allele frequency = 0.00081% (PM2). The variant has been reported in dbSNP (rs80359003) and has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 52401).

This variant changes 1 nucleotide in exon 16 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 several individuals affected with breast and/or ovarian cancer (PMID: 12673801, 22711857, 23633455, 24333842, 33113089, 33471991, Color internal data). This variant has been identified in families with suspected hereditary breast and ovarian cancer syndrome, including 21 families among the CIMBA participants (PMID: 11802209, 16528604, 29446198). This variant has been identified in 2/251434 chromosomes 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.Trp2586X variant in BRCA2 has been reported in at least 14 individuals with BRCA2-related cancer (Perkowska 2003, Willems-Jones 2012, George 2013, Li 2018, BIC database). It has also been identified in 2/113726 European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant leads to a premature termination codon at position 2586, which is predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). Another variant, c.7758G>A, resulting in the same amino acid change has been identified in individuals with BRCA2-related cancers and is classified as pathogenic by this laboratory. Additionally, this variant was classified as Pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 52401). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate, PS1.

The BRCA2 p.Trp2586X variant has been reported in 8/4826 proband chromosomes (frequency 0.002) of individuals with breast and/or ovarian cancer increasing the likelihood this variant is pathogenic, however, no normal population controls were included in these studies (Alsop 2012, Callahan 2007, Jonsson 2005, Meindl 2002, Perkowska 2003, Watson 2009, Weitzel 2005) It is reported in the BIC (x5) database as clinically significant. The variant leads to a premature stop codon at position 2586 which is predicted to cause premature truncation or an absent protein product and loss of function. Loss of function of the BRCA2 gene is an established disease mechanism for hereditary breast cancer. This variant is classified as pathogenic

The BRCA2 c.7757G>A variant is predicted to result in premature protein termination (p.Trp2586*). This variant was reported in individuals with breast cancer and/or ovarian cancer (Perkowska et al. 2003. PubMed ID: 12673801; Alsop et al. 2012. PubMed ID: 22711857; George et al. 2013. PubMed ID: 23633455; Conner et al. 2014. PubMed ID: 24333842; Supplemental Table 4, Li et al. 2018. PubMed ID: 29752822; Supplemental Table, Petridis et al. 2019. PubMed ID: 31263054) and in individuals with prostate cancer (Supplemental Table 2, Willems-Jones et al. 2012. PubMed ID: 23035815; Castro et al. 2013. PubMed ID: 23569316; Walker et al. 2014. PubMed ID: 25485004). This variant was also reported in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) database (Supplemental Table 1, Rebbeck et al. 2018. PubMed ID: 29446198). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is reported as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/52401/). Loss of function variants in BRCA2 are known to be pathogenic. Taken together, this variant is interpreted as pathogenic.