ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3545_3546del (p.Gln1181_Phe1182insTer) (rs80359388)

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Total submissions: 26
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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) RCV000031427 SCV000282379 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 RCV000044219 SCV000072232 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Phe1182*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs748852670, ExAC 0.006%). This variant has been observed in individuals affected with breast and ovarian cancer (PMID: 15131399, 24156927, 25884701, 20104584). This variant is also known as 3772delTT, c.3773delTT, and p.Phe1182Terfs in the literature. ClinVar contains an entry for this variant (Variation ID: 37846). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000074527 SCV000108612 pathogenic not provided 2020-11-04 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; Observed as heterozygous in individuals with a personal and/or family history of BRCA2-related cancers, and as compound heterozygous in an individual with Fanconi anemia (Lubinski 2004, Cavallone 2010, Tea 2014, Belanger 2015, Malric 2015, Shindo 2017); Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 3772delTT or 3773delTT; This variant is associated with the following publications: (PMID: 20104584, 21952622, 15131399, 25884701, 24156927, 21324516, 26986251, 25381700, 15382066, 20694749, 16905680, 28166811, 28767289, 21568838, 18042939, 17416853, 16825431, 16141007, 15796958, 15197194, 12677558, 9497246, 22430266, 26014432, 26295337, 29339979, 29084914, 30128899, 30609409, 30720243, 31851867, 31409081, 32255556)
Counsyl RCV000031427 SCV000154067 likely pathogenic Breast-ovarian cancer, familial 2 2014-01-31 criteria provided, single submitter literature only
Ambry Genetics RCV000131093 SCV000186023 pathogenic Hereditary cancer-predisposing syndrome 2018-11-21 criteria provided, single submitter clinical testing The c.3545_3546delTT pathogenic mutation (also known as p.F1182*), located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 3545 to 3546. This changes the amino acid from a phenylalanine to a stop codon within coding exon 10. This mutation has been well described in the literature and has been seen in multiple individuals with a personal and/or family history consistent with hereditary breast and ovarian cancer (HBOC) syndrome, including several French-Canadian families (Lubinski J et al. Fam. Cancer. 2004;3:1-10; Oros KK et al. Int. J. Cancer. 2004 Nov;112:411-9; Simard J et al. J. Med. Genet. 2007 Feb;44:107-21; Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40; Belanger MH et al. J. Ovarian Res. 2015 Mar;8:1; Labidi-Galy SI et al. Clin. Cancer Res. 2018 Jan;24(2):326-333). Of note, this alteration is also designated as 3773delTT and 3772delTT 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.
Ambry Genetics RCV000210566 SCV000262830 pathogenic Inborn genetic diseases 2014-06-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000074527 SCV000296692 pathogenic not provided 2020-01-21 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 at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031427 SCV000326880 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Department of Medical Genetics, Oslo University Hospital RCV000031427 SCV000605663 pathogenic Breast-ovarian cancer, familial 2 2015-07-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000044219 SCV000605795 pathogenic Hereditary breast and ovarian cancer syndrome 2019-04-24 criteria provided, single submitter clinical testing The p.Phe1182X variant in BRCA2 has been reported in >15 individuals with BRCA2-associated cancers (Breast Cancer Information Core (BIC) database, Lubinski 2004, Borg 2010, Tea 2014, Belanger 2015, Polsler 2016). It has also been identified in 5/113332 European chromosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant creates a premature termination codon at position 1182, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in HBOC. Furthermore, the p.Phe1182X variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282379.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. ACMG/AMP criteria applied: PVS1, PS4.
Color Health, Inc RCV000131093 SCV000683566 pathogenic Hereditary cancer-predisposing syndrome 2020-07-14 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals and families affected with breast and/or ovarian cancer (PMID: 15131399, 15382066, 20104584, 20694749, 21324516, 24156927, 29084914, 29339979) and in an individual affected with Fanconi anemia with a family history of early-onset breast cancer (PMID: 25381700). This variant has been identified in 5/250970 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.
GeneKor MSA RCV000074527 SCV000693564 pathogenic not provided 2020-01-01 criteria provided, single submitter clinical testing This sequence change deletes 2 nucleotide from exon 11 of the BRCA2 mRNA (c.3545_3546delTT), creating a premature translational stop signal at codon 1182 (p.Phe1182*). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic. This variant has been reported in the literature in individuals affected with breast and ovarian cancer (PMID: 15131399 24156927, 25884701, 20104584) and is also known as 3772delTT and c.3773delTT. The mutation database ClinVar contains entries for this variant (Variation ID: 37846).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000044219 SCV000694703 pathogenic Hereditary breast and ovarian cancer syndrome 2021-07-18 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.3545_3546delTT (p.Phe1182X) 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 2e-05 in 250970 control chromosomes. c.3545_3546delTT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000074527 SCV000883490 pathogenic not provided 2017-08-04 criteria provided, single submitter clinical testing The BRCA2 c.3545_3546delTT; p.Phe1182Ter variant (rs80359388), also known as 3772delTT and 3773delTT, has been reported in several individuals and families with breast and/or ovarian cancer (Belanger 2015, Borg 2010, Lubinski 2004, Tea 2014). It is reported in ClinVar as pathogenic (Variation ID: 37846), and observed in the general population with an overall allele frequency of 0.002 percent (5/245740 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or absent transcript. Taken together, c.3545_3546delTT is considered pathogenic. REFERENCES Link to ClinVar database for c.3545_3546delTT: https://www.ncbi.nlm.nih.gov/clinvar/variation/37846/ Belanger MH et al. A targeted analysis identifies a high frequency of BRCA1 and BRCA2 mutation carriers in women with ovarian cancer from a founder population. J Ovarian Res. 2015 Mar 27;8:1. Borg A et al. Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. Hum Mutat. 2010 Mar;31(3):E1200-40. Lubinski J et al. Cancer variation associated with the position of the mutation in the BRCA2 gene. Fam Cancer. 2004;3(1):1-10. Tea MK et al. Central European BRCA2 mutation carriers: birth cohort status correlates with onset of breast cancer. Maturitas. 2014 Jan;77(1):68-72.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000735540 SCV000902197 pathogenic Breast and/or ovarian cancer 2019-04-24 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000074527 SCV001446508 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001642309 SCV001854550 pathogenic Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2013-12-01 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000031427 SCV000054032 pathogenic Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031427 SCV000146255 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Division of Human Genetics,Medical University Innsbruck RCV000031427 SCV000212017 pathogenic Breast-ovarian cancer, familial 2 2015-02-11 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353741 SCV000591867 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The p.Phe1182X variant has been identified in 4 out of 5086 proband chromosomes (frequency 0.001) in individuals with unilateral, contralateral and familial breast and ovarian cancer phenotype; however no control chromosomes were included in these studies (Lubinski 2004, Borg 2010). It is listed in dbSNP database coming from a “clinical source” (ID#: rs80359388) however no frequency information was provided. The variant was identified in ClinVar from 6 sources in at least 23 individuals from different ethnic backgroungs (GeneDx, BIC, Ambry, and SCRP derived from Myriad reports all classify this variant as pathogenic; Counsyl classified this variant as Likely pathogenic). This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence and leads to a premature stop codon at position 1182. This alteration is predicted to cause a truncated or absent BRCA2 protein product and loss of function. Loss of function of the BRCA2 gene is an established disease mechanism in familial breast and ovarian cancer patients. In summary, based on the above information, this variant is classified as pathogenic.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735540 SCV000863678 pathogenic Breast and/or ovarian cancer 2016-04-07 no assertion criteria provided clinical testing
CZECANCA consortium RCV001391215 SCV001593131 pathogenic Carcinoma of pancreas 2021-03-04 no assertion criteria provided case-control
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000074527 SCV001739576 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000074527 SCV001905756 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000074527 SCV001928861 pathogenic not provided no assertion criteria provided clinical testing

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