Submissions for variant NM_000059.4(BRCA2):c.2254_2257del (p.Asp752fs)

dbSNP: rs80359326

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113027	SCV000300502	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
GeneDx	RCV000657223	SCV000778949	pathogenic	not provided	2021-11-04	criteria provided, single submitter	clinical testing	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; Not observed at significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 2482_2485delGACT and 2482del4; This variant is associated with the following publications: (PMID: 12070551, 26187060, 20960228, 17233897, 23996866, 28486781, 28828701, 25780794, 29409476, 30675319, 32733560, 33067490)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770716	SCV000902193	uncertain significance	Breast and/or ovarian cancer	2017-07-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001014946	SCV001175722	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-03	criteria provided, single submitter	clinical testing	The c.2254_2257delGACT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 2254 to 2257, causing a translational frameshift with a predicted alternate stop codon (p.D752Ffs*19). This mutation has been reported in multiple individuals diagnosed with breast cancer (El-Harith el-HA et al. Saudi Med J. 2002 Jun;23:700-4; Borg A et al. Hum Mutat. 2010 Mar;31:E1200-40; Abdel-Razeq H et al. BMC Cancer. 2018 02;18:152; Abdel-Razeq H et al. J Oncol. 2020 Jul;2020:8362179). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Of note, this alteration is also designated as 2482del4 in some 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496907	SCV002233865	pathogenic	Hereditary breast ovarian cancer syndrome	2024-09-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp752Phefs*19) 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 cancer (PMID: 12070551, 20104584, 29409476). This variant is also known as 2482delGACT, Stop770. ClinVar contains an entry for this variant (Variation ID: 51260). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000657223	SCV003813806	pathogenic	not provided	2022-03-10	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657223	SCV005624351	pathogenic	not provided	2024-01-05	criteria provided, single submitter	clinical testing	The BRCA2 c.2254_2257del (p.Asp752Phefs*19) variant (also known as 2482del4, 2482delGACT) 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 multiple individuals with breast cancer (PMIDs: 33471991 (2021), 34290354 (2021), 33067490 (2020), 32733560 (2020), 29409476 (2018), 20104584 (2010), 12070551 (2002)). 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.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113027	SCV000146021	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496907	SCV000587626	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research