ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.9076C>T (p.Gln3026Ter)

dbSNP: rs80359159
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Total submissions: 22
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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) RCV000031790 SCV000301347 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 RCV000045706 SCV000073719 pathogenic Hereditary breast ovarian cancer syndrome 2023-07-27 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 38207). For these reasons, this variant has been classified as Pathogenic. RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 11595708, 19016756, 22632462, 25863477, 26187060, 27732944, 28008555, 28205045). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln3026*) 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).
Ambry Genetics RCV000131038 SCV000185968 pathogenic Hereditary cancer-predisposing syndrome 2022-04-06 criteria provided, single submitter clinical testing The p.Q3026* pathogenic mutation (also known as c.9076C>T), located in coding exon 22 of the BRCA2 gene, results from a C to T substitution at nucleotide position 9076. This changes the amino acid from a glutamine to a stop codon within coding exon 22. This mutation has been identified in multiple hereditary breast and/or ovarian cancer families (Sekine M et al. Clin Cancer Res. 2001 Oct;7(10):3144-50; Arai M et al. J. Hum. Genet. 2018 Apr;63(4):447-457; Momozowa Y et al. Nat Commun 2018 10;9(1):4083). Of note, this mutation is also designated as 9304C>T 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031790 SCV000328043 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000413921 SCV000490440 pathogenic not provided 2024-08-20 criteria provided, single submitter clinical testing Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 9304C>T; This variant is associated with the following publications: (PMID: 22798144, 11149425, 33309985, 33057194, 36243179, 35982159, 28440963, 32980694, 32826389, 19016756, 25863477, 23893897, 26187060, 11595708, 28008555, 28205045, 27732944, 29439820, 30287823, 28111427, 29446198, 25525159, 31447099, 32710294, 30787465, 35741847, 31723001, 34645131, 29176636, 30350268, 22632462)
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency RCV000045706 SCV000586988 pathogenic Hereditary breast ovarian cancer syndrome 2017-04-18 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000031790 SCV000743358 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2014-10-08 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000031790 SCV000746275 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2017-12-03 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000413921 SCV000883483 pathogenic not provided 2017-05-31 criteria provided, single submitter clinical testing The BRCA2 c.9076C>T, p.Gln3026Ter variant (rs80359159) has been reported in a family with breast and ovarian cancer (Sekine 2001). Minigene analysis indicates that the variant generates a transcript that leads to a premature termination codon through a frameshift or nonsense codon, or a transcript lacking 2 exons and approximately 101 amino acids (Acedo 2012). The variant is classified as pathogenic in ClinVar (Variation ID: 38207), but not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). The variant introduces a premature termination codon, and is predicted to result in a truncated protein or an absent transcript. Based on the above information, the variant is classified as pathogenic. References: Acedo A et al. Comprehensive splicing functional analysis of DNA variants of the BRCA2 gene by hybrid minigenes. Breast Cancer Res. 2012; 14(3):R87. Sekine M et al. Mutational analysis of BRCA1 and BRCA2 and clinicopathologic analysis of ovarian cancer in 82 ovarian cancer families: two common founder mutations of BRCA1 in Japanese population. Clin Cancer Res. 2001; 7(10):3144-50.
Color Diagnostics, LLC DBA Color Health RCV000131038 SCV000911637 pathogenic Hereditary cancer-predisposing syndrome 2022-01-04 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 23 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A minigene splicing assay has shown partial splicing defect (PMID: 22632462). This variant has been reported in at least a dozen individuals affected with breast or ovarian cancer (PMID: 11149425, 19016756, 22798144, 28008555, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_001520), in families suspected of being affected with hereditary breast and ovarian cancer (PMID: 11595708, 25863477) and in individuals affected with pancreatic or prostate cancer (PMID: 27732944, 31214711, 32980694). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000045706 SCV000916964 pathogenic Hereditary breast ovarian cancer syndrome 2019-01-07 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9076C>T (p.Gln3026X) 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 (e.g. c.9093_9094delinsG/p.Thr3033fsX29, c.9097dupA/p.Thr3033fsX11). The variant was absent in 246292 control chromosomes (gnomAD). c.9076C>T has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Malone_2006, Kang_2015, Palmero_2018). These data indicate that the variant is very likely to be associated with disease. Co-occurrence with another pathogenic variant has been reported (BRCA2 c.6237_6238delGT, p.Leu2080ArgfsX4) possibly in a patient with Fanconi Anemia (BRCA Share database). One study showed this variant did not significantly affect splicing (Acedo_2012). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all classified this variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000045706 SCV000966961 pathogenic Hereditary breast ovarian cancer syndrome 2018-07-18 criteria provided, single submitter clinical testing The p.Gln3026X variant in BRCA2 has been reported in >10 individuals with BRCA2- associated cancers (Ikeda 2001, Sekine 2001, Sugano 2008, Kang 2015, Arai 2018). It was also absent from large population studies. This nonsense variant leads t o a premature termination codon at position 3026, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene i s an established disease mechanism in hereditary breast and ovarian cancer (HBOC ). In addition, this variant was classified as Pathogenic on Sep 8, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID 38207). In summary, the p.Gln 3026X variant meets criteria to be classified as pathogenic for HBOC in an autos omal dominant manner. ACMG/AMP criteria applied: PVS1, PS4_Moderate, PM2.
Research Institute, Aichi Cancer Center RCV000045706 SCV002503887 pathogenic Hereditary breast ovarian cancer syndrome 2022-02-01 criteria provided, single submitter research
Baylor Genetics RCV003473225 SCV004210348 pathogenic Familial cancer of breast 2024-02-14 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000413921 SCV005625340 pathogenic not provided 2024-04-15 criteria provided, single submitter clinical testing The BRCA2 c.9076C>T (p.Gln3026*) variant causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMIDs: 35741847 (2022), 34645131 (2022), 33471991 (2021), 32710294 (2021), 29907814 (2018), 29176636 (2018), 28205045 (2017), 25863477 (2015), 22798144 (2012), 19016756 (2008), 11595708 (2001)), including triple negative breast cancer (PMID: 30350268 (2018)) and male breast cancer (PMIDs: 30287823 (2018), 28008555 (2017)). Additionally, this variant has been reported in individuals with prostate cancer (PMID: 29439820 (2018)) and pancreatic cancer (PMID: 27732944 (2016)). Experimental studies show conflicting evidence of this variant's impact on splicing (PMIDs: 25525159 (2015), 22632462 (2012)). 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.
Sharing Clinical Reports Project (SCRP) RCV000031790 SCV000054398 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2013-01-29 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031790 SCV000147529 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2004-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001353572 SCV000592252 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The p.Gln3026X variant has been reported in 4 of 4712 proband chromosomes from individuals with breast or ovarian cancer (Sekine 2001, Sugano 2008, Kim 2012). This variant leads to a premature stop codon at position 3026, 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 hereditary breast and ovarian cancer 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000031790 SCV000733329 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735618 SCV000863756 pathogenic Breast and/or ovarian cancer 2014-07-30 no assertion criteria provided clinical testing
Laboratory for Genotyping Development, RIKEN RCV003162284 SCV002758401 pathogenic Gastric cancer 2021-07-01 no assertion criteria provided research
PreventionGenetics, part of Exact Sciences RCV004532464 SCV004121577 pathogenic BRCA2-related disorder 2024-08-28 no assertion criteria provided clinical testing The BRCA2 c.9076C>T variant is predicted to result in premature protein termination (p.Gln3026*). This variant was reported in multiple individuals with breast, ovarian cancer, or other cancers (see examples: Table 2, Sekine et al. 2001. PubMed ID: 11595708;  Momozawa et al. 2018. PubMed ID: 30287823; Figure 1 and Table S1, Park. 2017. PubMed ID: 28111427; Table 1, Antonarakis. 2018. PubMed ID: 29439820).  This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant is interpreted as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/38207/). Nonsense variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic.

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