Submissions for variant NM_000059.4(BRCA2):c.8285del (p.Pro2762fs)

dbSNP: rs397507972

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000256769	SCV000324637	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-10-18	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000256769	SCV000327850	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002426597	SCV002679184	pathogenic	Hereditary cancer-predisposing syndrome	2020-11-25	criteria provided, single submitter	clinical testing	The c.8285delC pathogenic mutation, located in coding exon 17 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 8285, causing a translational frameshift with a predicted alternate stop codon (p.P2762Lfs*15). This alteration (designated as 8513delC) has previously been reported in a family with HBOC related cancers in at least two generations and was identified in a large, worldwide study of BRCA1/2 mutation positive families (Litton JK et al. Cancer. 2012 Jan; 118(2):321-5; Rebbeck TR et al. Hum Mutat. 2018 05;39:593-620). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700327	SCV005203459	pathogenic	Hereditary breast ovarian cancer syndrome	2024-07-18	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8285delC (p.Pro2762LeufsX15), also reported as "8513delC", 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. The variant was absent in 248612 control chromosomes. c.8285delC has been reported in the literature in the heterozygous state in at least 1 individual affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Litton_2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 21913181). ClinVar contains an entry for this variant (Variation ID: 52540). Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004998159	SCV005625316	pathogenic	not provided	2024-01-25	criteria provided, single submitter	clinical testing	The BRCA2 c.8285del (p.Pro2762Leufs*15) variant alters the translational reading frame of the BRCA2 mRNA and is predicted to cause the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in several BRCA1/2 studies, however those identified with the variant have unspecified affected status (PMIDs: 29446198 (2018), 21913181 (2012)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV004700327	SCV005836286	pathogenic	Hereditary breast ovarian cancer syndrome	2024-08-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro2762Leufs*15) 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 breast and/or ovarian cancer (PMID: 21913181). This variant is also known as 8513delC. ClinVar contains an entry for this variant (Variation ID: 52540). For these reasons, this variant has been classified as Pathogenic.