ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4456_4459del (p.Val1486fs) (rs80359449)

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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 RCV000222405 SCV000275650 pathogenic Hereditary cancer-predisposing syndrome 2016-12-08 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) RCV000083106 SCV000146425 pathogenic Breast-ovarian cancer, familial 2 1998-08-25 no assertion criteria provided clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000083106 SCV000327036 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) RCV000083106 SCV000300748 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 RCV000212235 SCV000210752 pathogenic not provided 2018-01-23 criteria provided, single submitter clinical testing This deletion of four nucleotides in BRCA2 is denoted c.4456_4459delGTTA at the cDNA level and p.Val1486AsnfsX5 (V1486NfsX5) at the protein level. The normal sequence, with the bases that are deleted in brackets, is CATA[delGTTA]AACA. The deletion causes a frameshift, which changes a Valine to an Asparagine at codon 1486, and creates a premature stop codon at position 5 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.4456_4459delGTTA, previously reported as 4454_4457delTAGT, 4684del4 and 4682del4 using alternate nomenclature, has been reported in individuals with breast cancer, including male breast and early-onset disease (Verhoog 1999, Churpek 2015, Susswein 2016, Pritzlaff 2017). We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000044417 SCV000918859 pathogenic Hereditary breast and ovarian cancer syndrome 2017-10-05 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.4456_4459delGTTA (p.Val1486AsnfsX5) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.4471_4474delCTGA (p.Leu1491fsX12), c.4472_4475delTGAA (p.Leu1491fsX12), c.4478_4481delAAAG (p.Glu1493fsX10)). This variant has been reported in individuals and families affected by breast cancer in the literature (Verhoog 2001, Churpek 2014, Susswein 2015), but was absent in 30966 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000044417 SCV000072430 pathogenic Hereditary breast and ovarian cancer syndrome 2018-11-24 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val1486Asnfs*5) 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 several individuals affected with breast cancer (PMID: 10550133, 28008555, 26681312). In the literature, this variant is also known as 4684del4. ClinVar contains an entry for this variant (Variation ID: 51650). 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) RCV000083106 SCV000115180 pathogenic Breast-ovarian cancer, familial 2 2012-09-06 no assertion criteria provided clinical testing

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