ClinVar Miner

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

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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Ambry Genetics RCV000131093 SCV000186023 pathogenic Hereditary cancer-predisposing syndrome 2017-10-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Ambry Genetics RCV000210566 SCV000262830 pathogenic Inborn genetic diseases 2014-06-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Breast Cancer Information Core (BIC) (BRCA2) RCV000031427 SCV000146255 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000044219 SCV000219328 pathogenic Hereditary breast and ovarian cancer syndrome 2017-02-28 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000735540 SCV000902197 pathogenic Breast and/or ovarian cancer 2017-10-12 criteria provided, single submitter clinical testing
Color RCV000131093 SCV000683566 pathogenic Hereditary cancer-predisposing syndrome 2016-03-02 criteria provided, single submitter clinical testing
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
Counsyl RCV000031427 SCV000154067 likely pathogenic Breast-ovarian cancer, familial 2 2014-01-31 criteria provided, single submitter literature only
Department of Medical Genetics,Oslo University Hospital RCV000031427 SCV000605663 pathogenic Breast-ovarian cancer, familial 2 2015-07-01 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000044219 SCV000591867 pathogenic Hereditary breast and ovarian cancer syndrome 2014-10-30 criteria provided, single submitter clinical testing
Division Human Genetics,Medical University Innsbruck RCV000031427 SCV000212017 pathogenic Breast-ovarian cancer, familial 2 2015-02-11 no assertion criteria provided clinical testing
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.
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
GeneDx RCV000074527 SCV000108612 pathogenic not provided 2018-11-30 criteria provided, single submitter clinical testing This deletion of two nucleotides is denoted BRCA2 c.3545_3546delTT at the cDNA level and p.Phe1182Ter (F1182X) at the protein level. The normal sequence, with the bases that are deleted in brackets, is CAAT[delTT]GAAG. The deletion creates a nonsense variant, which changes a Phenylalanine to a premature stop codon. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.3545_3546delTT, previously reported as 3772delTT or 3773delTT using alternate nomenclature, has been reported in multiple individuals with a personal and/or family history of breast, ovarian, and/or pancreatic cancer (Lubinski 2004, Cavallone 2010, Tea 2014, Belanger 2015, Shindo 2017), and in the compound heterozygous state in at least one patient with Fanconi Anemia (Malric 2015). We consider this variant to be pathogenic.
GeneKor MSA RCV000074527 SCV000693564 pathogenic not provided 2017-11-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000044219 SCV000694703 pathogenic Hereditary breast and ovarian cancer syndrome 2017-06-09 criteria provided, single submitter clinical testing Variant summary: The c.3545_3546delTT (p.Phe1182X) variant in BRCA2 gene is a 2-bp deletion that creates a nonsense variant at codon 1182. This change is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The variant is present at a low frequency in large control population dataset of ExAC at a frequency 0.000033 (4/121246 chrs tested), which does not exceed exceed the estimated maximal expected allele frequency of a pathogenic variant (0.00075). The variant has been reported in numerous affected individuals via published reports and cited by reputable databases/clinical laboratories as Pathogenic. Taking together, the variant was classified as Pathogenic.
Invitae RCV000044219 SCV000072232 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-04 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 reported 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000044219 SCV000605795 pathogenic Hereditary breast and ovarian cancer syndrome 2016-10-04 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 4/66684 European chromosomes by the Exome Aggregation Consortium (ExAC, http ://exac.broadinstitute.org; dbSNP rs80359388); however, this frequency is low en ough 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 prot ein. Heterozygous loss of function of the BRCA2 gene is an established disease m echanism in HBOC. Furthermore, the p.Phe1182X variant was classified as Pathogen ic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000 282379.1). In summary, this variant meets criteria to be classified as pathogeni c for HBOC in an autosomal dominant manner.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000074527 SCV000296692 pathogenic not provided 2015-03-30 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031427 SCV000054032 pathogenic Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing

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