Submissions for variant NM_000059.4(BRCA2):c.7419_7420del (p.Cys2473_Glu2474delinsTer)

dbSNP: rs80359651

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031677	SCV000282442	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-22	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	RCV000031677	SCV000327653	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000506083	SCV000600746	pathogenic	not provided	2023-09-18	criteria provided, single submitter	clinical testing	This variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. In the published literature, this variant has been reported in individuals with hereditary breast and/or ovarian cancer (PMID: 14574155 (2003), 15955690 (2005), 34326862 (2021), 33471991 (2021), 33471991 (2021)). The frequency of this variant in the general population, 0.000004 (1/250976 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000031677	SCV000744517	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496947	SCV000916925	pathogenic	Hereditary breast ovarian cancer syndrome	2017-11-09	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.7419_7420delTG (p.Cys2473X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 1/245822 control chromosomes (gnomAD) at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). Multiple publications have cited the variant in affected individuals and indicate the variant is a Dutch founder mutation. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496947	SCV001580391	pathogenic	Hereditary breast ovarian cancer syndrome	2024-12-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys2473*) 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 (rs80359651, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 14574155, 15955690, 16683254, 24285858). This variant is also known as c.7647delTG. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001524804	SCV001734763	pathogenic	Hereditary cancer-predisposing syndrome	2020-08-24	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 14 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 and families affected with hereditary breast and/or ovarian cancer (PMID: 14574155, 15955690, 16683254) and is a common disease-causing mutation in the Dutch population (PMID: 25103822). This variant has been identified in 1/250976 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.
Ambry Genetics	RCV001524804	SCV003879282	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-15	criteria provided, single submitter	clinical testing	The c.7419_7420delTG pathogenic mutation, located in coding exon 13 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 7419 to 7420, causing a translational frameshift with a predicted alternate stop codon (p.C2473*). This alteration has been previously identified in multiple individuals and families with early onset breast, ovarian, fallopian tube, and/or primary peritoneal cancer (Piek JM et al. Fam Cancer, 2003;2:73-8; Wárlám-Rodenhuis CC et al. Eur J Cancer, 2005 Jul;41:1409-15). Of note, this alteration is also designated as 7647delTG 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.
Baylor Genetics	RCV003460527	SCV004216165	pathogenic	Familial cancer of breast	2023-05-03	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031677	SCV000054284	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2009-01-15	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031677	SCV000147079	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496947	SCV000587892	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000031677	SCV000733299	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358336	SCV001554040	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Cys2473* variant was identified in dbSNP (ID: rs80359651) as “With Pathogenic allele”, ClinVar (as pathogenic by ENIGMA, CIMBA, Quest Diagnostics, Erasmus Medical Center, University Medical Center Groningen, Women's College Hospital, COGR, SCRP, and BIC), and LOVD 3.0 (76x as pathogenic). The variant was not identified in UMD-LSDB, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The variant was also reported in the literature as a founder mutation in the Northern Netherlands, however the frequency of this variant in an affected population was not provided (Vos 2014). The c.7419_7420del variant leads to a premature stop codon at position 2473 which is predicted to lead to 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 (HBOC) 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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000506083	SCV001797428	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000506083	SCV001906123	pathogenic	not provided		no assertion criteria provided	clinical testing