ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2658_2659del (p.Asn886fs) (rs397507291)

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Total submissions: 7
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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) RCV000031377 SCV000300548 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 RCV000482987 SCV000569842 pathogenic not provided 2016-03-31 criteria provided, single submitter clinical testing This deletion of 2 nucleotides in BRCA2 is denoted c.2658_2659delTG at the cDNA level and p.Asn886LysfsX3 (N886KfsX3) at the protein level. The normal sequence, with the bases that are deleted in braces, is ACAA[TG]AGAA. The deletion causes a frameshift which changes an Asparagine to a Lysine at codon 886, 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000482987 SCV001133720 pathogenic not provided 2019-02-14 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 not found in general population data.
Ambry Genetics RCV001016231 SCV001177162 pathogenic Hereditary cancer-predisposing syndrome 2018-04-18 criteria provided, single submitter clinical testing The c.2658_2659delTG pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 2658 to 2659, causing a translational frameshift with a predicted alternate stop codon (p.N886Kfs*3). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193144 SCV001361807 likely pathogenic Hereditary breast and ovarian cancer syndrome 2019-02-14 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.2658_2659delTG (p.Asn886LysfsX3) 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.2808delA (p.Lys936fsX24), c.2808_2811delACAA (p.Ala938fsX21), c.2830A>T (p.Lys944X)). The variant allele was found at a frequency of 4.4e-06 in 226710 control chromosomes (gnomAD). To our knowledge, no occurrence of c.2658_2659delTG in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV001193144 SCV001421395 pathogenic Hereditary breast and ovarian cancer syndrome 2019-10-16 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn886Lysfs*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 been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 37796). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031377 SCV000053982 pathogenic Breast-ovarian cancer, familial 2 2009-05-05 no assertion criteria provided clinical testing

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