ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8754+5G>A (rs81002813)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031765 SCV000327957 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000571571 SCV000666018 likely pathogenic Hereditary cancer-predisposing syndrome 2016-03-21 criteria provided, single submitter clinical testing The c.8754+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 20 in the BRCA2 gene. This alteration has been reported in a patient diagnosed with early-onset breast cancerwho had afamily history of breast cancer (VreeswijkMP et al.HumMutat. 2009 Jan;30(1):107-14). Multiple splicing assays have shown this alteration results in an aberrant transcript which retains 46 nucleotides from intron 20 and wouldcausea translationalframeshiftwith a predicted alternate stop codon (VreeswijkMP et al.HumMutat. 2009 Jan;30(1):107-14;HendriksG et al.HumMutat. 2014 Nov;35(11):1382-91;AcedoA et al.HumMutat. 2015 Feb;36(2):210-21). In addition, Hendriks et al. (2014) used a functional complementation assay inmouse-embryonic stem (mES) cells which showed that the alteration could not complement the lethality ofmBrca2-deficient mES cells.This variant was previously reported in the SNPDatabase as rs81002813, but was absent from population-based cohorts in the NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project databases. To date, this alteration has been detected with an allele frequency of approximately 0.0004% (greater than 225000alleles tested) in our clinical cohort.This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site.Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000031765 SCV000743352 pathogenic Breast-ovarian cancer, familial 2 2017-07-28 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031765 SCV000054373 pathogenic Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031765 SCV000147449 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000031765 SCV000733323 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing

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