ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7719dup (p.Trp2574fs) (rs80359676)

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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) RCV000113808 SCV000301197 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 RCV000568775 SCV000661350 pathogenic Hereditary cancer-predisposing syndrome 2016-08-24 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)
Integrated Genetics/Laboratory Corporation of America RCV000587385 SCV000695097 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-25 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.7719dupA (p.Trp2574Metfs) 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 nearby and downstream of this position have been classified as pathogenic by our laboratory (e.g., c.7721G>A [p.Trp2574X]; c.7757G>A [p.Trp2586X]; c.7758G>A [p.Trp2586X]), indicating the region is a mutational hotspot and truncations beyond the variant of interest are responsible for disease. One in silico tool predicts a damaging outcome for this variant. This variant is absent from the large control database ExAC (0/121342 control chromosomes). However, it has been reported in one HBOC patient in the BIC database, although this patient also carried a potentially pathogenic BRCA1 variant (BIC classified both BRCA2 c.7719dupA and the co-occurring BRCA1 c.66_67delAG [p.Leu22_Glu23LeuValfs] as pathogenic; LCA depicts the c.66_67delAG under correct HGVS nomenclature as c.68_69delAG currently scored as a DV). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000587385 SCV000946202 pathogenic Hereditary breast and ovarian cancer syndrome 2018-11-01 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp2574Metfs*10) 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: 126155). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113808 SCV000147166 pathogenic Breast-ovarian cancer, familial 2 1999-05-04 no assertion criteria provided clinical testing

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