Submissions for variant NM_000059.4(BRCA2):c.2786dup (p.Leu929fs)

dbSNP: rs80359347

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077694	SCV000300555	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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077694	SCV000326766	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000569923	SCV000661367	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-16	criteria provided, single submitter	clinical testing	The c.2786dupT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of T at nucleotide position 2786, causing a translational frameshift with a predicted alternate stop codon (p.L929Ffs*7). This alteration has been identified in a cohort of high-risk breast/ovarian cancer patients (Castéra L et al. Eur J Hum Genet, 2014 Nov;22:1305-13). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	RCV000496679	SCV001588195	pathogenic	Hereditary breast ovarian cancer syndrome	2024-11-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu929Phefs*7) 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 hereditary breast and ovarian cancer (PMID: 15131399, 24549055). This variant is also known as c.3014insT. ClinVar contains an entry for this variant (Variation ID: 51345). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001576401	SCV001803579	pathogenic	not provided	2021-08-28	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 in large population cohorts (Lek et al., 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 24549055, 26023681, 15131399)
National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	RCV000496679	SCV002522185	pathogenic	Hereditary breast ovarian cancer syndrome	2021-08-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001576401	SCV004219555	pathogenic	not provided	2021-12-18	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in patients with hereditary breast and ovarian cancer, and prostate cancer (PMIDs: 32853339 (2021), 24549055 (2014), 15131399 (2004)). Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496679	SCV004241875	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-07	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2786dupT (p.Leu929PhefsX7) results in a premature termination codon and is expected to cause absence of the protein due to nonsense mediated decay, a commonly known mechanism for disease. The variant was absent in 250880 control chromosomes (gnomAD). c.2786dupT has been reported in the literature in at least one individual affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Castera_2014). These data suggest that the variant is very likely to be associated with disease. 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: 24549055). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
All of Us Research Program, National Institutes of Health	RCV000077694	SCV004845056	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-08	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 11 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 with a personal or family history of breast and/or ovarian cancer (PMID: 15131399, 24549055, 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.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000077694	SCV005416065	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		criteria provided, single submitter	clinical testing	PM2_Supporting+PVS1+PS4_Supporting
Sharing Clinical Reports Project (SCRP)	RCV000077694	SCV000109497	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2008-07-24	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077694	SCV000146108	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	RCV000496679	SCV000587642	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research