ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2480dup (p.Asn827fs) (rs397507286)

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Total submissions: 6
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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) RCV000031368 SCV000300524 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics RCV000130443 SCV000185307 pathogenic Hereditary cancer-predisposing syndrome 2017-08-23 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000381040 SCV000329134 pathogenic not provided 2018-01-22 criteria provided, single submitter clinical testing This duplication of one nucleotide in BRCA2 is denoted c.2480dupA at the cDNA level and p.Asn827LysfsX3 (N827KfsX3) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA2 2708dupA. The normal sequence, with the base that is duplicated in braces, is GAAA[A]TTAT. The duplication causes a frameshift, which changes an Asparagine to a Lysine at codon 827, and creates a premature stop codon at position 3 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.
Invitae RCV000550883 SCV000635224 pathogenic Hereditary breast and ovarian cancer syndrome 2018-08-03 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn827Lysfs*3) 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: 37787). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000550883 SCV000694608 pathogenic Hereditary breast and ovarian cancer syndrome 2019-06-17 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.2480dupA (p.Asn827LysfsX3) 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. The variant was absent in 239098 control chromosomes (gnomAD). c.2480dupA has been reported in the literature to be found in an internal sample at Ambry Genetics (LaDuca_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories and an expert panel (ENIGMA)(evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031368 SCV000053973 pathogenic Breast-ovarian cancer, familial 2 2009-06-09 no assertion criteria provided clinical testing

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