ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5217_5220del (p.Thr1738_Tyr1739insTer) (rs80359494)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219606 SCV000274521 pathogenic Hereditary cancer-predisposing syndrome 2014-07-07 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113400 SCV000146569 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000219606 SCV000688921 pathogenic Hereditary cancer-predisposing syndrome 2017-07-27 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000113400 SCV000327175 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) RCV000113400 SCV000300847 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 RCV000497280 SCV000210761 pathogenic not provided 2014-03-18 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.5217_5220delTTTATTT at the cDNA level and p.Tyr1739Ter (Y1739X) at the protein level. The substitution creates a nonsense variant, changing a Tyrosine to a premature stop codon (TAT>TAA). The normal sequence, with the bases that are deleted in brackets, is CTTA[TTTA]AGT. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Of note, BRCA2 c.5217_5220delTTTATTT is also known as 5445del4 using alternate nomenclature. This variant has been reported in a family with breast and prostate cancers (Stuppia 2003) and is listed as clinically important in the Breast Cancer Information Core (BIC) database. We therefore consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000507175 SCV000694843 pathogenic Hereditary breast and ovarian cancer syndrome 2017-01-19 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.5217_5220delTTTA (p.Tyr1739fs) 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. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP) and has been reported in multiple affected individuals via publications. In addition, it seems to be in a mutation hot spot, where other pathogenic variants have been reported such as c.5218_5223del7, c.5213_5216del4, and c.5217_5221del5. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000507175 SCV000605820 pathogenic Hereditary breast and ovarian cancer syndrome 2017-07-20 criteria provided, single submitter clinical testing The p.Tyr1739X variant in BRCA2 has been reported 5 individuals with BRCA2-assoc iated cancers (Stuppia 2003, Susswein 2015, Breast Cancer Information Core (BIC) ). It was also absent from large population studies, though the ability of these studies to accurately detect indels may be limited. This nonsense variant is a result of a deletion of 4 bases, which creates a premature termination codon at position 1739. This alteration is then predicted to lead to a truncated or absen t protein. Heterozygous loss of function of the BRCA2 gene is an established dis ease mechanism in hereditary breast and ovarian cancer (HBOC). In addition, this variant was classified as pathogenic on September 8, 2016 by the ClinGen-approv ed ENIGMA expert panel (ClinVar SCV000300847.2). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based on predicted impact to the protein and absence from controls.

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