Submissions for variant NM_000059.4(BRCA2):c.8961_8964del (p.Ser2988fs)

dbSNP: rs80359734

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077457	SCV000301325	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045673	SCV000073686	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser2988Phefs*12) 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: 10923033, 12872265). This variant is also known as 9189del4. ClinVar contains an entry for this variant (Variation ID: 52714). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000220005	SCV000276007	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-07	criteria provided, single submitter	clinical testing	The c.8961_8964delGAGT pathogenic mutation, located in coding exon 22 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 8961 to 8964, causing a translational frameshift with a predicted alternate stop codon (p.S2988Ffs*12). This mutation has been detected in multiple individuals with hereditary breast and/or ovarian cancer (Stuppia L et al. Hum. Mutat. 2003;22(2):178-9; Yang et al. Breast Cancer Res. Treat. 2017 Oct;165(3):687-697; Rebbeck et al. Hum. Mutat. 2018 05;39(5):593-620; Wang et al. BMC Cancer 2018 03;18:315; Ow et al. PLoS ONE 2019 Mar;14:e0213746). In one functional study using minigene assays, this mutation was predicted to disrupt the SF2/ASF and SRp55 protein complexes and create an exonic splicing silencer (Acedo A et al. Breast Cancer Res. 2012;14(3):R87). Of note, this alteration is also designated as 9189del4 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.
GeneDx	RCV000215485	SCV000279326	pathogenic	not provided	2023-01-05	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 (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 9189_9192delGAGT; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Stuppia et al., 2003; Tutt et al., 2010; Yang et al., 2017; Wang et al., 2018); This variant is associated with the following publications: (PMID: 22632462, 24578176, 20609467, 12872265, 29566657, 30875412, 30787465, 33573335, 28664506)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077457	SCV000328014	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000045673	SCV000592244	pathogenic	Hereditary breast ovarian cancer syndrome	2016-08-10	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000215485	SCV000600834	pathogenic	not provided	2017-03-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045673	SCV001774536	pathogenic	Hereditary breast ovarian cancer syndrome	2021-07-26	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8961_8964delGAGT (p.Ser2988PhefsX12) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250792 control chromosomes (gnomAD). c.8961_8964delGAGT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Stuppia_2003, Tutt_2010, Rebbeck_2018). These data indicate 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. Seven ClinVar submitters (evaluation after 2014), including one expert panel (ENIGMA), cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000045673	SCV002025865	pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000220005	SCV002053308	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-12	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 23 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast/ovarian cancer (PMID: 12872265, 20609467, 27153395, 28664506, 29566657). 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV002255125	SCV002526680	pathogenic	Familial cancer of breast	2022-04-29	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP
Sema4, Sema4	RCV000220005	SCV002531994	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-23	criteria provided, single submitter	curation
Baylor Genetics	RCV002255125	SCV004216177	pathogenic	Familial cancer of breast	2023-04-22	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000077457	SCV004242399	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-28	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM5_STR,PM2_SUP
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004795974	SCV005417919	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3; Familial prostate cancer		criteria provided, single submitter	clinical testing	PVS1+PM2+PS4_Moderate
Sharing Clinical Reports Project (SCRP)	RCV000077457	SCV000109255	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2006-03-24	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077457	SCV000147501	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	RCV000045673	SCV000587983	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research