ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8970G>A (p.Trp2990Ter) (rs80359149)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000565595 SCV000668530 pathogenic Hereditary cancer-predisposing syndrome 2017-02-16 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)
Breast Cancer Information Core (BIC) (BRCA2) RCV000114026 SCV000147504 pathogenic Breast-ovarian cancer, familial 2 1998-08-25 no assertion criteria provided clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000114026 SCV000328016 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000114026 SCV000301327 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 RCV000657750 SCV000779502 pathogenic not provided 2018-01-31 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8970G>A at the cDNA level and p.Trp2990Ter (W2990X) at the protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon (TGG>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not been reported in the literature to our knowledge, an alternate nucleotide change that causes the same protein truncation, 8969>A, was observed in breast cancer patient (Ellingson 2015). Based on currently available evidence, we consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000045675 SCV000695197 pathogenic Hereditary breast and ovarian cancer syndrome 2017-05-26 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.8970G>A (p.Trp2990X) 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.This variant is absent in 121066 control chromosomes (ExAC). A publication cites the variant in an affected individual, however, another variant, c.8969G>A, which causes the same nonsense mutation, has been reported in multiple publications and reputable databases/clinical laboratories and classified as "pathogenic." In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as "Pathogenic."
Invitae RCV000045675 SCV000073688 pathogenic Hereditary breast and ovarian cancer syndrome 2015-09-03 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 2990 (p.Trp2990*). It is expected to result in an absent or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic. This particular truncation has been reported in an individual with breast cancer (PMID: 10923033). In addition, a different nucleotide change (c.8969G>A) that results in the same truncation (p.2990*) has been reported in an individual with breast cancer (PMID: 22632462). For these reasons, this variant has been classified as Pathogenic.

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