ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6761_6762del (p.Phe2254fs) (rs80359624)

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Total submissions: 9
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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) RCV000113639 SCV000301105 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000045042 SCV000073055 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Phe2254Tyrfs*6) 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 an individual affected with breast cancer (PMID: 28814288). ClinVar contains an entry for this variant (Variation ID: 52178). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000222656 SCV000279230 pathogenic not provided 2018-08-23 criteria provided, single submitter clinical testing This deletion of two nucleotides in BRCA2 is denoted c.6761_6762delTT at the cDNA level and p.Phe2254TyrfsX6 (F2254YfsX6) at the protein level. The normal sequence, with the bases that are deleted in brackets, is CTTT[delTT]ACAT. The deletion causes a frameshift, which changes a Phenylalanine to a Tyrosine at codon 2254, and creates a premature stop codon at position 6 of the new reading frame. It is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Also published as BRCA2 c.6758_6759del (p.L2253fs) using alternate nomenclature, this variant has been reported in at least one individual with early-onset breast cancer and in another individual who underwent testing for Hereditary Breast and Ovarian Cancer syndrome (Seymour 2016, Maxwell 2017). We consider this variant to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000113639 SCV000327516 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000563851 SCV000668527 pathogenic Hereditary cancer-predisposing syndrome 2017-04-17 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)
Color RCV000563851 SCV000683807 pathogenic Hereditary cancer-predisposing syndrome 2016-09-09 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000222656 SCV000887889 pathogenic not provided 2018-02-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000045042 SCV000916835 pathogenic Hereditary breast and ovarian cancer syndrome 2019-03-18 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.6761_6762delTT (p.Phe2254TyrfsX6) 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 (eg. c.6944_6947delTAAA (p.Ile2315fsX12), c.6952C>T (p.Arg2318X), and c.6997_6998delGT (p.Val2333fsX6)). The variant was absent in 246160 control chromosomes (gnomAD). Multiple publications, c.6761_6762delTT, have cited the variant in affected individuals including one individual that was homozygous for the variant (Dougherty_2017, Maxwell_2017, Seymour_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113639 SCV000146925 pathogenic Breast-ovarian cancer, familial 2 2000-06-12 no assertion criteria provided clinical testing

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