ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4398_4402del (p.Leu1466fs) (rs80359444)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131078 SCV000186008 pathogenic Hereditary cancer-predisposing syndrome 2018-03-22 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) RCV000083104 SCV000146417 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000131078 SCV000683615 pathogenic Hereditary cancer-predisposing syndrome 2017-05-22 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000083104 SCV000327023 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000083104 SCV000489178 pathogenic Breast-ovarian cancer, familial 2 2016-08-30 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000044404 SCV000591902 pathogenic Hereditary breast and ovarian cancer syndrome 2015-06-16 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000083104 SCV000282391 pathogenic Breast-ovarian cancer, familial 2 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000160288 SCV000210749 pathogenic not provided 2018-04-26 criteria provided, single submitter clinical testing This deletion of five nucleotides in BRCA2 is denoted c.4398_4402delACATT at the cDNA level and p.Leu1466PhefsX2 (L1466FfsX2) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AATT[delACATT]CTGA. The deletion causes a frameshift which changes a Leucine to a Phenylalanine at codon 1466 and creates a premature stop codon at position 2 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.4398_4402delACATT, previously reported as 4625_4629delACATT and 1465_1467del using alternate nomenclature, has been observed in individuals with ovarian and prostate cancer (Agalliu 2007, Cunningham 2014, Song 2014, Natarajan 2016). We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000044404 SCV000694767 pathogenic Hereditary breast and ovarian cancer syndrome 2017-05-01 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.4398_4402delACATT (p.Leu1466Phefs) 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.4449delA (p.Asp1484fs) and c.4552delG (p.Glu1518fs)). This variant was found in 1/122244 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). This variant has been reported in multiple HBOC patients via publications, although one family, George_2016 does suggest lack of co-segregation with disease (affected paternal cousin without the variant) and/or reduced penetrance (unaffected father of the proband carries the variant). However, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000044404 SCV000072417 pathogenic Hereditary breast and ovarian cancer syndrome 2018-10-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu1466Phefs*2) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs755956766, ExAC 0.002%). This variant has been reported in individuals affected with breast, ovarian, and prostate cancer (PMID: 17700570, 24504028, 26681312, 27831900, 24728189, 27406733). This variant is also known as 4625_4629delACATT and 1465_1467del in the literature. ClinVar contains an entry for this variant (Variation ID: 51640). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Michigan Medical Genetics Laboratories,University of Michigan RCV000083104 SCV000195984 pathogenic Breast-ovarian cancer, familial 2 2014-11-03 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000083104 SCV000296657 pathogenic Breast-ovarian cancer, familial 2 2015-11-18 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160288 SCV000887815 pathogenic not provided 2015-11-18 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000083104 SCV000115178 pathogenic Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing

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