ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8954-5A>G (rs886040949)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000562165 SCV000665309 likely pathogenic Hereditary cancer-predisposing syndrome 2017-02-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Functionally-validated splicing mutation,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Moderate segregation with disease (at least 3 informative meioses) for rare diseases.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000258499 SCV000328012 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000461006 SCV000592239 pathogenic Hereditary breast and ovarian cancer syndrome 2012-05-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000461006 SCV000695196 likely pathogenic Hereditary breast and ovarian cancer syndrome 2016-12-19 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.8954-5A>G variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict an alteration on normal splicing, which is confirmed by functional studies which shows the variant incudes aberrant splicing of intron 22 with the retention of its last 4 bp, which is predicted to result in out of frame product (de Garibay_2014, Menendez_2012, Santos_2014). This variant is absent in 120924 control chromosomes, but was reported in numerous affected individuals in the literature, including one family in which 1 carrier unaffected, two families with one non-carrier in each family had HBOC. These families show some level of non-segregation. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic.
Invitae RCV000461006 SCV000549814 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-11-29 criteria provided, single submitter clinical testing This sequence change falls in intron 22 of the BRCA2 gene. It does not directly change the encoded amino acid sequence of the BRCA2 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families affected with hereditary breast and/or ovarian cancer (PMID: 21735045, 24607278, 24916970, 23479189). ClinVar contains an entry for this variant (Variation ID: 267712). Experimental studies have shown that this variant causes a splicing defect leading to premature truncation due to partial intron retention (PMID: 21735045, 24607278, 24123850). In summary, this variant is a rare intronic change that has been shown to disrupt mRNA splicing. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000461006 SCV000587982 likely pathogenic Hereditary breast and ovarian cancer syndrome 2015-12-17 no assertion criteria provided research

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