Submissions for variant NM_000059.4(BRCA2):c.3160_3163del (p.Asp1054fs)

dbSNP: rs80359371

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031405	SCV000282378	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.
Ambry Genetics	RCV000162917	SCV000213404	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-07	criteria provided, single submitter	clinical testing	The c.3160_3163delGATA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 3160 to 3163, causing a translational frameshift with a predicted alternate stop codon (p.D1054Ifs*5). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031405	SCV000326822	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000486228	SCV000568463	pathogenic	not provided	2022-10-06	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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in women with personal and/or family history of breast cancer (Gao et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 3388_3391delGATA; This variant is associated with the following publications: (PMID: 14973102, 31825140, 21702907)
Color Diagnostics, LLC DBA Color Health	RCV000162917	SCV000905007	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-17	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides 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 detected in at least one individual affected with breast cancer and has been reported in one family among the CIMBA participants (PMID: 29446198; Color internal data). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000486228	SCV001133741	pathogenic	not provided	2023-12-05	criteria provided, single submitter	clinical testing	The BRCA2 c.3160_3163del (p.Asp1054Ilefs*5) variant (also known as 3388del4, 3159_3162delAGAT) 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 personal and/or family history of breast/ovarian and unspecified hereditary cancer (PMIDs: 29446198 (2018), 28281021 (2017)). 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	RCV000496672	SCV001585165	pathogenic	Hereditary breast ovarian cancer syndrome	2024-12-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp1054Ilefs*5) 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 BRCA2-related conditions (PMID: 10923033, 21520333). ClinVar contains an entry for this variant (Variation ID: 37824). For these reasons, this variant has been classified as Pathogenic.
All of Us Research Program, National Institutes of Health	RCV000031405	SCV004845113	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-15	criteria provided, single submitter	clinical testing	The c.3160_3163del (p.Asp1054Ilefs*5) variant in the BRCA2 gene is located on the exon 11 and is predicted to cause shift of reading frame that introduces a premature translation termination codon (p.Asp1054Ilefs*5), resulting in an absent or disrupted protein product. The variant has been reported in individuals with breast and/or ovarian cancer (PMID: 31853058, 28281021). Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 8988179, 11897832, 29446198). The variant is reported in ClinVar as pathogenic (ID: 37824) and reviewed by the expert panel. The variant is absent in the general population database (gnomAD). Therefore, the c.3160_3163del (p.Asp1054Ilefs*5) variant of BRCA2 has been classified as pathogenic.
Baylor Genetics	RCV004566769	SCV005059077	pathogenic	Familial cancer of breast	2024-02-06	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004795941	SCV005416869	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	PM2_Supporting+PVS1+PS4_Supporting
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000486228	SCV005875738	pathogenic	not provided	2024-09-10	criteria provided, single submitter	clinical testing	The BRCA2 c.3160_3163del; p.Asp1054IlefsTer5 variant (rs80359371, ClinVar Variation ID: 37824) is reported in the literature in cohorts with suspicion of breast and ovarian cancer (Li 2020, Rebbeck 2018). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant causes a frameshift by deleting four nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Li H et al. Classification of variants of uncertain significance in BRCA1 and BRCA2 using personal and family history of cancer from individuals in a large hereditary cancer multigene panel testing cohort. Genet Med. 2020 Apr;22(4):701-708. PMID: 31853058. Rebbeck TR et al. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat. 2018 May;39(5):593-620. PMID: 29446198.
Sharing Clinical Reports Project (SCRP)	RCV000031405	SCV000054010	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2010-02-11	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031405	SCV000146180	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	RCV000496672	SCV000587659	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research