ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.6275_6276del (rs11571658)

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Total submissions: 30
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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) RCV000009903 SCV000282422 pathogenic Breast-ovarian cancer, familial 2 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000044884 SCV000072897 pathogenic Hereditary breast and ovarian cancer syndrome 2020-11-01 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu2092Profs*7) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs11571658, ExAC 0.009%). This variant has been observed in individuals affected with breast, ovarian, and prostate cancer (PMID: 8524414, 22009639, 21324516, 22006311, 20736950, 23199084), and has been proposed to be a European founder variant (PMID: 23199084). This variant is also known as 6503delTT in the literature. ClinVar contains an entry for this variant (Variation ID: 9318). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000009903 SCV000154072 pathogenic Breast-ovarian cancer, familial 2 2014-02-18 criteria provided, single submitter literature only
Ambry Genetics RCV000131029 SCV000185959 pathogenic Hereditary cancer-predisposing syndrome 2018-11-12 criteria provided, single submitter clinical testing The c.6275_6276delTT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 2 nucleotides between positions 6275 and 6276, causing a translational frameshift with a predicted alternate stop codon (p.L2092Pfs*7). This mutation has been detected in multiple individuals with breast and/or ovarian cancer (Khitto G et al. Hum. Hered. 2001;52:55-8; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Walsh T et al. Proc. Natl. Acad. Sci. USA. 2011 Nov;108:18032-7; Bayraktar S et al. Cancer. 2012 Mar;118:1515-22; Higgs JE et al. J. Med. Genet. 2015 Sep;52:642-5; de Juan I et al. Fam. Cancer. 2015 Dec;14:505-13; Maxwell KN et al. Am. J. Hum. Genet. 2016 May;98:801-817; Fostira F et al. Breast Cancer Res. Treat. 2018 May;169:105-113; Wang YA et al. BMC Cancer. 2018 03;18:315). Of note, this alteration is also designated as 6503delTT 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 RCV000160300 SCV000210777 pathogenic not provided 2019-01-04 criteria provided, single submitter clinical testing This deletion of two nucleotides in BRCA2 is denoted c.6275_6276delTT at the cDNA level and p.Leu2092ProfsX7 (L2092PfsX7) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AGTC[delTT]CACT. The deletion causes a frameshift, which changes a Leucine to a Proline at codon 2092, and creates a premature stop codon at position 7 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.6275_6276delTT, previously reported as BRCA2 6503delTT, has been observed in numerous families with Hereditary Breast and Ovarian Cancer (Wooster 1995, Edwards 2010, Walsh 2011, Zhang 2011, Bayraktar 2012, Higgs 2015). We consider this variant to be pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000160300 SCV000225153 pathogenic not provided 2018-05-25 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131029 SCV000292149 pathogenic Hereditary cancer-predisposing syndrome 2020-08-24 criteria provided, single submitter clinical testing This variant deletes 2 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 reported in individuals affected with breast and/or ovarian cancer and is a common disease-causing mutation in the European population (PMID: 21324516, 23199084, 23479189, 24156927, 26026974, 29566657). This variant has been identified in 10/274924 chromosomes 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 RCV000160300 SCV000296690 pathogenic not provided 2019-05-04 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in multiple symptomatic patients, and found in general population data that is consistent with pathogenicity.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000009903 SCV000327378 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Genologica Medica RCV000009903 SCV000577963 pathogenic Breast-ovarian cancer, familial 2 2017-01-01 criteria provided, single submitter clinical testing
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000044884 SCV000586966 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-18 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine,Queen's University RCV000044884 SCV000588108 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000044884 SCV000694953 pathogenic Hereditary breast and ovarian cancer syndrome 2016-07-22 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.6275_6276delTT (p.Leu2092Profs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 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.p.N2135fs). One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/120912 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). This variant has been reported in numerous Br/Ov cancer patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000009903 SCV000744484 pathogenic Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000009903 SCV000839912 pathogenic Breast-ovarian cancer, familial 2 2017-10-12 criteria provided, single submitter clinical testing This c.6275_6276del (p.Leu2092Profs*7) variant in exon 11 of the BRCA2 gene is a deletion of 2 nucleotides and is predicted to cause loss of function of normal protein through mRNA decay or producing a truncated protein, which is a known disease mechanism for this gene. This particular variant (also known as 6503delTT) has been reported in multiple individuals affected with breast, ovarian, and prostate cancer (PMID: 8524414, 22009639, 21324516, 22006311, 20736950, 23199084). The c.6275_6276del (p.Leu2092Profs*7) variant in BRCA2 gene is classified as pathogenic (Atteeq Rehman 10-12-2017).
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000160300 SCV000883475 pathogenic not provided 2018-05-21 criteria provided, single submitter clinical testing The BRCA2 c.6275_6276delTT; p.Leu2092fs variant (rs11571658), also known as 6503delTT for traditional nomenclature, is reported in individuals with breast, ovarian, or prostate cancer (Bayraktar 2012, de Juan 2015, Edwards 2010, Walsh 2011, Wooster 1995, Zhang 2011). This variant is reported multiple times in ClinVar (Variation ID: 9318), and found in the general population with a low overall allele frequency of 0.003% (9/269698 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting 2 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 Bayraktar S et al. Predictive factors for BRCA1/BRCA2 mutations in women with ductal carcinoma in situ. Cancer. 2012 Mar 15;118(6):1515-22. de Juan I et al. BRCA1 and BRCA2 mutations in males with familial breast and ovarian cancer syndrome. Results of a Spanish multicenter study. Fam Cancer. 2015 Dec;14(4):505-13. Edwards SM et al. Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis. Br J Cancer. 2010 Sep 7;103(6):918-24. Walsh T et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18032-7. Wooster R et al. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995 Dec 21-28;378(6559):789-92. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011 May 1;121(2):353-7.
Academic Department of Medical Genetics, University of Cambridge RCV000131029 SCV000992213 likely pathogenic Hereditary cancer-predisposing syndrome 2018-01-26 criteria provided, single submitter research Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002251 SCV001160127 pathogenic not specified 2018-11-28 criteria provided, single submitter clinical testing The BRCA2 c.6275_6276delTT; p.Leu2092fs variant (rs11571658), also known as 6503delTT in traditional nomenclature, is reported in multiple individuals affected with breast, ovarian, or prostate cancer (Bayraktar 2012, de Juan 2015, Edwards 2010, Walsh 2011, Wooster 1995, Zhang 2011). This variant is reported as pathogenic by numerous laboratories in ClinVar (Variation ID: 9318), and it is found in the general population with a low overall allele frequency of 0.004% (10/274924 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting two 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: Bayraktar S et al. Predictive factors for BRCA1/BRCA2 mutations in women with ductal carcinoma in situ. Cancer. 2012 Mar 15;118(6):1515-22. de Juan I et al. BRCA1 and BRCA2 mutations in males with familial breast and ovarian cancer syndrome. Results of a Spanish multicenter study. Fam Cancer. 2015 Dec;14(4):505-13. Edwards SM et al. Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis. Br J Cancer. 2010 Sep 7;103(6):918-24. Walsh T et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18032-7. Wooster R et al. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995 Dec 21-28;378(6559):789-92. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011 May 1;121(2):353-7.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000160300 SCV001248279 pathogenic not provided 2018-09-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000009903 SCV001429107 pathogenic Breast-ovarian cancer, familial 2 2018-02-14 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000160300 SCV001450151 pathogenic not provided 2015-06-17 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000160300 SCV001714432 pathogenic not provided 2019-07-04 criteria provided, single submitter clinical testing PVS1, PM2, PP5
OMIM RCV000009903 SCV000030124 pathogenic Breast-ovarian cancer, familial 2 2001-01-01 no assertion criteria provided literature only
Sharing Clinical Reports Project (SCRP) RCV000009903 SCV000054219 pathogenic Breast-ovarian cancer, familial 2 2013-10-16 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000009903 SCV000146807 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Pathway Genomics RCV000009903 SCV000189898 pathogenic Breast-ovarian cancer, familial 2 2014-07-24 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000044884 SCV000587833 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000160300 SCV000592039 uncertain significance not provided no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000009903 SCV000733279 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735583 SCV000863721 pathogenic Breast and/or ovarian cancer 2015-08-18 no assertion criteria provided clinical testing

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