Total submissions: 22
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Evidence- |
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 |
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 |
RCV000031790 | SCV000328043 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2015-10-02 | criteria provided, single submitter | clinical testing | |
Gene |
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, |
RCV000045706 | SCV000586988 | pathogenic | Hereditary breast ovarian cancer syndrome | 2017-04-18 | criteria provided, single submitter | clinical testing | |
Genome Diagnostics Laboratory, |
RCV000031790 | SCV000743358 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2014-10-08 | criteria provided, single submitter | clinical testing | |
Genomic Research Center, |
RCV000031790 | SCV000746275 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2017-12-03 | criteria provided, single submitter | clinical testing | |
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, |
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, |
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, |
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, |
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 |
RCV000031790 | SCV000054398 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2013-01-29 | no assertion criteria provided | clinical testing | |
Breast Cancer Information Core |
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, |
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, |
RCV000031790 | SCV000733329 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | no assertion criteria provided | clinical testing | ||
Foulkes Cancer Genetics LDI, |
RCV000735618 | SCV000863756 | pathogenic | Breast and/or ovarian cancer | 2014-07-30 | no assertion criteria provided | clinical testing | |
Laboratory for Genotyping Development, |
RCV003162284 | SCV002758401 | pathogenic | Gastric cancer | 2021-07-01 | no assertion criteria provided | research | |
Prevention |
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. |