ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4638del (p.Phe1546fs) (rs80359462)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163113 SCV000213623 pathogenic Hereditary cancer-predisposing syndrome 2017-09-12 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)
Breast Cancer Information Core (BIC) (BRCA2) RCV000031496 SCV000146460 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 RCV000735552 SCV000901111 pathogenic Breast and/or ovarian cancer 2017-09-19 criteria provided, single submitter clinical testing
Color RCV000163113 SCV000683640 pathogenic Hereditary cancer-predisposing syndrome 2017-03-24 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031496 SCV000327064 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031496 SCV000488820 pathogenic Breast-ovarian cancer, familial 2 2016-06-24 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine,Queen's University RCV000044457 SCV000588093 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-20 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031496 SCV000300775 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 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 RCV000735552 SCV000863690 pathogenic Breast and/or ovarian cancer 2015-03-18 no assertion criteria provided clinical testing
GeneDx RCV000255077 SCV000321461 pathogenic not provided 2018-05-16 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA2 is denoted c.4638delT at the cDNA level and p.Phe1546LeufsX22 (F1546LfsX22) at the protein level. This deletion is also known as BRCA2 4862delT and 4866delT using alternate nomenclature. The normal sequence, with the base that is deleted in brackets, is CTTTT[delT]GATG. The deletion causes a frameshift, which changes a Phenylalanine to a Leucine at codon 1546, and creates a premature stop codon at position 22 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.4638delT has been reported as a disease-causing variant in patients with personal histories of with breast, ovarian, and prostate cancer, respectively (Anglian Breast Cancer Study Group 2000, Zhang 2011, Ellingson 2015, Pritchard 2016). We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000044457 SCV000694789 pathogenic Hereditary breast and ovarian cancer syndrome 2017-06-16 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.4638delT (p.Phe1546Leufs) 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. c.4647_4650delAGAG/p.Lys1549fs). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 120716 control chromosomes. This variant has been reported in multiple affected individuals and multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000044457 SCV000072470 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Phe1546Leufs*22) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 11044354, 14647210, 15131399, 17148771, 21324516, 26296701). This variant is also known as 4862delT and 4866delT in the literature. ClinVar contains an entry for this variant (Variation ID: 37915). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000255077 SCV000600598 pathogenic not provided 2016-09-22 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000044457 SCV000587720 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000031496 SCV000054101 pathogenic Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing

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