ClinVar Genomic variation as it relates to human health

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

​The c.470_474delAGTCA (also known as 698del5, c.470del5, and p.K157Sfs*24) pathogenic mutation located in coding exon 4 of the BRCA2 gene, results from a deletion of 5 nucleotides between nucleotide positions 470 and 474, causing a translational frameshift with a predicted alternate stop codon. In addition to causing premature protein truncation, functional splicing analysis demonstrates that this alteration also results in exon 5 skipping via disruption of the exonic splicing enhancer (Sanz DJ et al. Clin. Cancer Res. 2010; 16:1957-67). This alteration was previously reported in one individual with breast cancer at age 32 from a Chinese cohort of 489 breast cancer patients with a diagnosis under the age of 35 or a family history of breast and/or ovarian cancer ( Li WF et al. Breast Cancer Res. Treat. 2008; 110:99-109). In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).

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, while also shown to result in aberrant splicing resulting in multiple transcripts including deletion exon 5 (Sanz 2010, Stauffer 2020); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Li 2008, Cao 2016, Weren 2016, Sun 2017); Published functional studies demonstrate a damaging effect: reduced cell viability and hypersensitivity to DNA damaging agents (Stauffer 2020); 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; Also known as 698_702del or 469_473del; This variant is associated with the following publications: (PMID: 30720863, 28176296, 30702160, 31174498, 27060066, 29487695, 28294317, 26295337, 33563323, 32926049, 26852015, 32623769, 30883759, 31825140, 17851763, 20215541, 22632462, 32393813, 28724667, 27767231)

For these reasons, this variant has been classified as Pathogenic. Studies have shown this premature translational stop signal is associated with skipping of exon 5, but one or more of the resulting mRNA isoform(s) may be naturally occurring (PMID: 20215541, 27060066). ClinVar contains an entry for this variant (Variation ID: 51701). This variant is also known as 698del5, Stop 180, c.469_473del. This premature translational stop signal has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 17851763, 27767231, 28294317, 28724667, 29487695). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys157Serfs*24) 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 deletes 5 nucleotides in exon 5 of the BRCA2 protein, 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 11 individuals affected with breast or ovarian cancer (PMID: 17851763, 28294317, 29487695, 31174498, doi:10.1515/tjb-2019-0424) and has been identified in 5 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.