ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4631dupA (p.Asn1544Lysfs) (rs80359460)

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Total submissions: 12
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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) RCV000031493 SCV000300774 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000044456 SCV000072469 pathogenic Hereditary breast and ovarian cancer syndrome 2018-08-07 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn1544Lysfs*4) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs771851449, ExAC 0.002%). This variant has been reported in individuals affected with breast/ovarian cancer, and an individual undergoing testing for Lynch syndrome  (PMID: 17688236, 23683081, 25980754, 24728189). This variant is also known as 4859insA in the literature. ClinVar contains an entry for this variant (Variation ID: 37912). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000132322 SCV000187408 pathogenic Hereditary cancer-predisposing syndrome 2017-05-30 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 RCV000388617 SCV000296705 pathogenic not provided 2019-08-23 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031493 SCV000327062 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000388617 SCV000329608 pathogenic not provided 2017-11-15 criteria provided, single submitter clinical testing This duplication of one nucleotide in BRCA2 is denoted c.4631dupA at the cDNA level and p.Asn1544LysfsX4 (N1544KfsX4) at the protein level. The normal sequence, with the base that is duplicated in braces, is GAAAA[A]CCTT. The duplication causes a frameshift, which changes an Asparagine to a Lysine at codon 1544, and creates a premature stop codon at position 4 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.4631dupA, previously published as BRCA2 4859dupA using alternate nomenclature, has been reported in association with Hereditary Breast Ovarian Cancer Syndrome (Ramus 2007, Blay 2013). We consider this variant to be pathogenic.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769695 SCV000901110 pathogenic Breast and/or ovarian cancer 2017-04-23 criteria provided, single submitter clinical testing
Color RCV000132322 SCV000911166 pathogenic Hereditary cancer-predisposing syndrome 2015-04-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000044456 SCV000916854 pathogenic Hereditary breast and ovarian cancer syndrome 2018-02-19 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.4631dupA (p.Asn1544LysfsX4) 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 245418 control chromosomes (gnomAD). The c.4631dupA variant has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) classify the variant as "pathogenic," in addition, multiple reliable databases also classify the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031493 SCV000054098 pathogenic Breast-ovarian cancer, familial 2 2007-08-15 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031493 SCV000146458 pathogenic Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000044456 SCV000587718 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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