ClinVar Genomic variation as it relates to human health

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

This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, the variant has been reported in individuals with breast, ovarian, and prostate cancer in the published literature (PMID: 17148771 (2006), 21324516 (2011), 21952622 (2011), 23569316 (2013), 24728189 (2014), 29625052 (2018)). This variant has not been reported in large, multi-ethnic general populations. Based on the available information, the variant is classified as pathogenic.

Variant summary: BRCA2 c.1265delA (p.Asn422IlefsX8) 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 248930 control chromosomes (gnomAD). c.1265delA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer (examples: Risch_2006, , Kote-Jarai_2011, Song_2014 and NHGRI BIC database). These data indicate that the variant is very likely to be associated with disease. One expert panel and eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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 BRCA2-related cancers (Risch et al., 2006; Kote-Jarai et al., 2011; Zhang et al., 2011, Song et al., 2014); Not observed in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 1493delA; This variant is associated with the following publications: (PMID: 28831036, 21952622, 24728189, 30720243, 29922827, 28888541, 26689913, 21324516, 17148771, 23569316, 27225637, 29625052, 31948886, 30787465, 32090079, 29446198, 20104584)

The BRCA2 c.1265delA; p.Asn422fs variant (rs80359273), also known as 1493delA, has been reported in multiple individuals with prostate or ovarian cancers (Kote-Jarai 2011, Risch 2006, Song 2014, Zhang 2011). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant introduces a frameshift, and is predicted to result in a truncated protein or an absent transcript. Based on available information, the p.Asn422fs variant is classified as pathogenic. References: Kote-Jarai Z et al. BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients. Br J Cancer. 2011; 105(8):1230-4. Risch H et al. Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. J Natl Cancer Inst. 2006; 98(23):1694-706. Song H et al. The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. Hum Mol Genet. 2014 Sep 1;23(17):4703-9. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011; 121(2):353-7.

This variant deletes 1 nucleotide in exon 10 of the BRCA2 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 been reported in 4 individuals affected with breast or ovarian cancer (PMID: 8640236, 17148771, 21324516, 24728189, 29625052). This variant has been identified in 1/240472 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.

This sequence change creates a premature translational stop signal (p.Asn422Ilefs*8) 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 (rs757511530, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ovarian cancer and prostate cancer (PMID: 17148771, 21324516, 21952622, 23569316, 24728189). This variant is also known as 1493delA. ClinVar contains an entry for this variant (Variation ID: 37735). For these reasons, this variant has been classified as Pathogenic.

The c.1265del (p.Asn422Ilefs*8) variant in the BRCA2 gene is located on the exon 10 and is predicted to result in shift of reading frame that introduces a premature translation termination codon (p.Asn422Ilefs*8), resulting in an absent or disrupted protein product. Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 29446198, 11897832, 8988179). This variant has been reported in multiple individuals with breast/ovarian/prostate cancer (PMID: 21952622, 29446198, 24728189). The variant is reported in ClinVar as pathogenic (ID: 37735) and reviewed by the expert panel. The variant is absent in the general population database (gnomAD). Therefore, the c.1265del (p.Asn422Ilefs*8) variant of BRCA2 has been classified as pathogenic.

The c.1265delA pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 1265, causing a translational frameshift with a predicted alternate stop codon (p.N422Ifs*8). This mutation has been reported in multiple patients with breast, ovarian, or prostate cancer (Risch HA et al. J. Natl. Cancer Inst. 2006 Dec;98:1694-706; Kote-Jarai Z et al. Br. J. Cancer 2011 Oct;105:1230-4; Castro E et al. J. Clin. Oncol. 2013 May;31(14):1748-57; Song H et al. Hum. Mol. Genet. 2014 Sep 1;23(17):4703-9; Lu C et al. Nat Commun. 2015 Dec 22;6:10086; Maxwell KN et al. Nat Commun, 2017 08;8:319). Of note, this alteration is also designated as 1493delA and c.1262delA 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.