ClinVar Genomic variation as it relates to human health

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

The BRCA2 c.8575del (p.Gln2859Lysfs*4) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 11304778 (2001), 20104584 (2010), and 23704984 (2013)), or prostate cancer (PMID: 27433846 (2016)). The frequency of this variant in the general population, 0.00016 (1/6120 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is 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; 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 8803delC; This variant is associated with the following publications: (PMID: 11504767, 30720243, 25685387, 20104584, 10359546, 16760289, 11304778, 18703817, 21324516, 26360800, 26833046, 27083775, 27433846, 31723001, 33087929, 30787465, 32570879, 34308366, 28888541, 34399810, 34887416, 33804961, 31060593, 29446198, 33471991)

Variant summary: BRCA2 c.8575delC (p.Gln2859LysfsX4) 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 4e-06 in 251220 control chromosomes. c.8575delC 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 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

PVS1, PM2, PS4

This sequence change creates a premature translational stop signal (p.Gln2859Lysfs*4) 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 (rs80359718, gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with prostate cancer and breast cancer (PMID: 11304778, 20104584, 23704984, 26360800, 27083775, 27433846). This variant is also known as 8803delC. ClinVar contains an entry for this variant (Variation ID: 38169). For these reasons, this variant has been classified as Pathogenic.

This variant deletes 1 nucleotide in exon 20 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 individuals affected with breast and/or ovarian cancer (PMID: 11304778, 16847550, 17148771, 18703817, 20104584, 21324516, 23704984, 25395318, 27083775), and prostate cancer (PMID: 27433846). This variant has been identified in 1/251220 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 c.8575del (p.Gln2859Lysfs*4) variant in the BRCA2 gene is located on the exon 20 and is predicted to cause shift of reading frame that introduces a premature translation termination codon (p.Gln2859Lysfs*4), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with breast/ovarian/prostate cancer (PMID: 34680878, 36999648, 34399810, 25685387, 31060593, 32098980). Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 8988179, 11897832, 29446198). The variant is reported in ClinVar as pathogenic (ID: 38169) and reviewed by the expert panel. The variant is rare in the general population according to gnomAD (1/251220). Therefore, the c.8575del (p.Gln2859Lysfs*4) variant of BRCA2 has been classified as pathogenic.

The p.Gln2859LysfsX4 variant in BRCA2 has been reported in >20 individuals with BRCA2-related cancers (Martin 2001, Pritchard 2016, Roed Nielsen 2016, BIC database). It was absent from large population databases. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 2859 and leads to a premature termination codon 4 amino acids downstream. This alteration is then 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). Additionally, this variant was classified as Pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 38169). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4.

The c.8575delC pathogenic mutation, located in coding exon 19 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 8575, causing a translational frameshift with a predicted alternate stop codon (p.Q2859Kfs*4). This mutation has been reported in several individuals diagnosed with hereditary breast and ovarian cancer (HBOC) syndrome (Peto J et al. J. Natl. Cancer Inst. 1999 Jun;91:943-9; Risch HA et al. J Natl Cancer Inst, 2006 Dec;98:1694-706; Giannini G et al. Breast Cancer Res. Treat. 2006 Nov;100:83-91; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Seifert BA et al. Clin Cancer Res, 2016 Aug;22:4087-4094; Roed Nielsen H et al. Acta Oncol. 2016 Sep;55:38-44; Nguyen-Dumont T et al. BMC Cancer, 2018 02;18:165; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Petridis C et al. Breast Cancer Res, 2019 05;21:58; Dorling et al. N Engl J Med. 2021 02;384:428-439). This mutation has also been identified in 1/692 men with metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53), as well as an individual with lymphoma (Sprissler R et al. Cancers (Basel), 2020 Jun;12). Of note, this alteration is also designated as 8803delC 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.

PVS1; PM5_PTC_Strong

The BRCA2 p.Gln2859LysfsX4 deletion variant was identified in 3 of 4874 proband chromosomes from individuals with breast or ovarian cancer (Borg 2010, Loman 2001, Martin 2001). The variant was also identified in dbSNP (ID: rs80359718) “With pathogenic allele”, HGMD, LOVD, and the BIC database (19X as a variant with clinical importance). The p.Gln2859LysfsX4 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 2859 and leads to a premature stop codon 4 codons downstream. This alteration is then predicted to result in 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.