ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4472_4475del (p.Leu1491fs) (rs80359452)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000213725 SCV000276320 pathogenic Hereditary cancer-predisposing syndrome 2017-06-23 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)
Breast Cancer Information Core (BIC) (BRCA2) RCV000031487 SCV000146429 pathogenic Breast-ovarian cancer, familial 2 2002-06-20 no assertion criteria provided clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031487 SCV000327040 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031487 SCV000300752 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000519823 SCV000617099 pathogenic not provided 2017-03-06 criteria provided, single submitter clinical testing This deletion of four nucleotides in BRCA2 is denoted c.4472_4475delTGAA at the cDNA level and p.Leu1491GlnfsX12 (L1491QfsX12) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA2 4700delTGAA or 4700del4. The normal sequence, with the bases that are deleted in brackets, is ATAC[delTGAA]AGAA. The deletion causes a frameshift, which changes a Leucine to a Glutamine at codon 1491, and creates a premature stop codon at position 12 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 4472_4475delTGAA has been observed in association with ovarian and prostate cancer (Song 2014, Pritchard 2016). We consider this variant to be pathogenic.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000031487 SCV000839909 pathogenic Breast-ovarian cancer, familial 2 2018-04-27 criteria provided, single submitter clinical testing A heterozygous 4472_4475delTGAA (p.Leu1491Glnfs*12) likely pathogenic variant in the BRCA2 gene was detected in this individual. This variant has been previously described in an individual with prostate cancer and epithelial ovarian cancer (PMID: 27433846, 24504028). Therefore, we consider this variant to be pathogenic. [yunyun, 2018-04-10]
Integrated Genetics/Laboratory Corporation of America RCV000044420 SCV000694774 pathogenic Hereditary breast and ovarian cancer syndrome 2016-08-08 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.4472_4475delTGAA (p.Leu1491Glnfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If this variant escapes NMD, it is predicted to truncate helical, OB, and Tower domains (Interpro). Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Arg3128X, c.9672dupA, p.Tyr3308X, etc). This variant is absent in approximately 123088 control chromosomes but has been reported in multiple patients with breast and/or ovarian cancer in literature and clinical databases. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as a Disease Variant/Pathogenic.
Invitae RCV000044420 SCV000072433 pathogenic Hereditary breast and ovarian cancer syndrome 2018-11-04 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu1491Glnfs*12) 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: 24504028, 24728189). ClinVar contains an entry for this variant (Variation ID: 37906). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031487 SCV000054092 pathogenic Breast-ovarian cancer, familial 2 2012-07-06 no assertion criteria provided clinical testing

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