ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.9097del (p.Thr3033fs)

dbSNP: rs397507419
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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031792 SCV000301349 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 RCV000031792 SCV000328045 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031792 SCV000489485 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2016-10-10 criteria provided, single submitter clinical testing
Ambry Genetics RCV000566875 SCV000665044 pathogenic Hereditary cancer-predisposing syndrome 2022-03-23 criteria provided, single submitter clinical testing The c.9097delA pathogenic mutation, located in coding exon 22 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 9097, causing a translational frameshift with a predicted alternate stop codon (p.T3033Lfs*29). This mutation has been reported in multiple individuals with hereditary breast and/or ovarian cancer (van der Hout AH et al. Hum. Mutat., 2006 Jul;27:654-66; Kang E et al. Breast Cancer Res. Treat., 2015 May;151:157-68; Caux-Moncoutier V et al. Hum. Mutat. 2011 Mar;32(3):325-34). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589165 SCV000695207 pathogenic Hereditary breast ovarian cancer syndrome 2022-03-21 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9097delA (p.Thr3033LeufsX29) 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 allele was found at a frequency of 1.2e-05 in 245952 control chromosomes. c.9097delA has been reported in the literature in numerous individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. 11 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV000657170 SCV000778891 pathogenic not provided 2018-08-17 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA2 is denoted c.9097delA at the cDNA level and p.Thr3033LeufsX29 (T3033LfsX29) at the protein level. Using alternate nomenclature, this variant would also be defined as BRCA2 9090delA or BRCA2 9325delA. The normal sequence, with the base that is deleted in brackets, is CAAAAAAA[delA]CTCA. The deletion causes a frameshift which changes a Threonine to a Leucine at codon 3033, and creates a premature stop codon at position 29 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.9097delA has been observed in numerous breast and/or ovarian cancer probands and families (van der Hout 2006, Caux-Moncoutier 2011, Miolo 2009, Ang 2007, Kang 2014, Peixoto 2014, Wong 2015). We consider this variant to be pathogenic.
Mendelics RCV000589165 SCV000838893 pathogenic Hereditary breast ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000566875 SCV000905025 pathogenic Hereditary cancer-predisposing syndrome 2021-11-15 criteria provided, single submitter clinical testing This variant deletes 1 nucleotide 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 detected in at least five individuals affected with breast cancer or breast and ovarian cancer (PMID: 18006916, 19818148, 26221963, 28993434; 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.
Mendelics RCV000031792 SCV001139247 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2019-05-28 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000657170 SCV001469463 pathogenic not provided 2020-08-02 criteria provided, single submitter clinical testing This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals affected with breast and/or ovarian cancer in the published literature (PMID: 28993434 (2018), 16683254 (2006)). Based on the available information, this variant is classified as pathogenic.
Invitae RCV000589165 SCV001591683 pathogenic Hereditary breast ovarian cancer syndrome 2023-12-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Thr3033Leufs*29) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 16683254, 21120943, 24578186, 24916970, 25863477, 26187060). ClinVar contains an entry for this variant (Variation ID: 38209). For these reasons, this variant has been classified as Pathogenic.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000657170 SCV002010294 pathogenic not provided 2021-11-03 criteria provided, single submitter clinical testing
Preventiongenetics, part of Exact Sciences RCV003407383 SCV004116026 pathogenic BRCA2-related condition 2023-01-23 criteria provided, single submitter clinical testing The BRCA2 c.9097delA variant is predicted to result in a frameshift and premature protein termination (p.Thr3033Leufs*29). This variant has been reported in several individuals with breast cancer (van der Hout et al 2006. PubMed ID: 16683254; Santonocito C et al 2020. PubMed ID: 32438681) and it is classified as pathogenic by over ten submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/38209/). This variant is documented in 0.0056% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32954022-CA-C). Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics RCV003473226 SCV004210459 pathogenic Familial cancer of breast 2022-11-02 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV003473226 SCV004244359 pathogenic Familial cancer of breast 2024-01-25 criteria provided, single submitter clinical testing Criteria applied: PVS1,PM5_STR
Sharing Clinical Reports Project (SCRP) RCV000031792 SCV000054400 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2012-05-01 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000657170 SCV001742763 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute RCV000657170 SCV001905996 pathogenic not provided no assertion criteria provided clinical testing

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