ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4808dupA (p.Asn1603Lysfs) (rs80359466)

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Total submissions: 5
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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) RCV000113345 SCV000300785 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 RCV000283062 SCV000329821 pathogenic not provided 2019-01-11 criteria provided, single submitter clinical testing This duplication of one nucleotide in BRCA2 is denoted c.4808dupA at the cDNA level and p.Asn1603LysfsX6 (N1603KfsX6) at the protein level. The normal sequence, with the base that is duplicated in brackets, is TAAAA[dupA]CCTT. The duplication causes a frameshift which changes an Asparagine to a Lysine at codon 1603, and creates a premature stop codon at position 6 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.4808dupA, also defined as 5036dupA and 5032insA by alternate nomenclature, has been reported in at least one family with hereditary breast and ovarian cancer (Gayther 1997). We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000781065 SCV000918869 pathogenic Hereditary breast and ovarian cancer syndrome 2019-01-22 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.4808dupA (p.Asn1603LysfsX6) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.4876_4877delAA, p.Asn1626fsX12; c.4936_4939delGAAA, p.Glu1646fsX23; c.4965C>G, p.Tyr1655X). The variant allele was found at a frequency of 8.2e-06 in 245372 control chromosomes (gnomAD). c.4808dupA has been reported in the literature in a family affected with Hereditary Breast and Ovarian Cancer (Gayther_1997). Two ClinVar submissions from a clinical diagnostic laboratory and a reputable database (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics RCV001023086 SCV001184908 pathogenic Hereditary cancer-predisposing syndrome 2017-06-16 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Breast Cancer Information Core (BIC) (BRCA2) RCV000113345 SCV000146485 pathogenic Breast-ovarian cancer, familial 2 2002-06-20 no assertion criteria provided clinical testing

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