ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.407del (p.Asn136fs) (rs80359425)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131981 SCV000187039 pathogenic Hereditary cancer-predisposing syndrome 2018-01-11 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) RCV000031457 SCV000146777 pathogenic Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Color RCV000131981 SCV000903713 pathogenic Hereditary cancer-predisposing syndrome 2017-11-06 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031457 SCV000326967 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Department of Medical Genetics,Oslo University Hospital RCV000031457 SCV000605660 pathogenic Breast-ovarian cancer, familial 2 2015-07-01 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031457 SCV000300319 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 RCV000255242 SCV000321444 pathogenic not provided 2017-01-05 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA2 is denoted c.407delA at the cDNA level and p.Asn136IlefsX16 (N136IfsX16) at the protein level. The normal sequence, with the base that is deleted in brackets, is CTAA[delA]TTCT. The deletion causes a frameshift, which changes an Asparagine to an Isoleucine at codon 136, and creates a premature stop codon at position 16 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000044342 SCV000918833 pathogenic Hereditary breast and ovarian cancer syndrome 2018-05-22 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.407delA (p.Asn136IlefsX16) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 244892 control chromosomes. c.407delA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Schrader 2016, Mutter 2017, Weigelt 2017, Heramb 2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating truncated/absent protein and loss of interaction with PALB2 and RAD51 (Weigelt 2017). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000044342 SCV000072355 pathogenic Hereditary breast and ovarian cancer syndrome 2018-06-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn136Ilefs*16) 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 not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 37876). 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 RCV000031457 SCV000267728 pathogenic Breast-ovarian cancer, familial 2 2016-04-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000255242 SCV000296688 pathogenic not provided 2015-11-28 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000044342 SCV000587546 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000031457 SCV000054062 pathogenic Breast-ovarian cancer, familial 2 2012-04-12 no assertion criteria provided clinical testing

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