ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4647_4650del (p.Lys1549fs) (rs397507734)

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Total submissions: 7
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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) RCV000238961 SCV000300777 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics RCV000165672 SCV000216410 pathogenic Hereditary cancer-predisposing syndrome 2017-06-07 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)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000238961 SCV000296641 pathogenic Breast-ovarian cancer, familial 2 2015-07-25 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000238961 SCV000327065 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588302 SCV000694791 pathogenic Hereditary breast and ovarian cancer syndrome 2016-06-06 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.4647_4650delAGAG (p.Lys1549Asnfs) 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. One in silico tool predicts a damaging outcome for this variant. This frameshift variant is located in close proximity to other known pathogenic variants, such as c.4638_4638delT (p.Phe1546Leufs), c.4648G>T (p.Glu1550Ter), c.4631_4631delA (p.Asn1544Thrfs), and c.4631_4632insA (p.Asn1544fs). These variants have been reported in UMD, BIC, ARUP and HGMD at least 33 times with biological significance "5 - Causal", indicating that the variant of interest is located in a mutational hot spot. This variant is absent in 120552 control chromosomes while it was reported in an early onset breast cancer case indicating pathogenicity. In addition, reputable databases (ARUP, UMD) and a clinical diagnostic laboratory (via ClinVar) classified the variant as pathogenic. The variant of interest shows very strong evidence for pathogenicity: it is a truncating variant, located in a mutational hot spot, absent from controls (ExAC), and reported in patients via publications/databases with a classification of "pathogenic." Therefore, taken together, the variant of interest is classified as Pathogenic.
GeneDx RCV000657173 SCV000778894 pathogenic not provided 2018-06-07 criteria provided, single submitter clinical testing This deletion of four nucleotides in BRCA2 is denoted c.4647_4650delAGAG at the cDNA level and p.Lys1549AsnfsX18 (K1549NfsX18) at the protein level. The normal sequence, with the bases that are deleted in brackets, is GAAAA[delAGAG]CAAG. The deletion causes a frameshift which changes a Lysine to an Asparagine at codon 1549, and creates a premature stop codon at position 18 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.4647_4650delAGAG, also reported as 4875del4 or 4875_4878delAGAG using alternate nomenclature, has been identified in individuals with early onset breast cancer and/or meeting criteria for multi-gene panel testing (Plaschke 2000, Yurgelun 2015). We consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000657173 SCV000889056 pathogenic not provided 2015-07-25 criteria provided, single submitter clinical testing

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