ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Breast Cancer Information Core (BIC) (BRCA2) RCV000113345 SCV000146485 pathogenic Breast-ovarian cancer, familial 2 2002-06-20 no assertion criteria provided clinical testing
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 2017-11-21 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.4808dupA (p.Asn1603LysfsX6) 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. 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). One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/245372 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant has been reported in at least one HBOC family in the literature (Gayther_1997). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

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