ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.8954-5A>G (rs886040949)

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Total submissions: 9
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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 RCV000258499 SCV000328012 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
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.
Ambry Genetics RCV000562165 SCV000665309 likely pathogenic Hereditary cancer-predisposing syndrome 2020-10-07 criteria provided, single submitter clinical testing The c.8954-5A>G intronic variant results from an A to G substitution 5 nucleotides upstream from coding exon 22 in the BRCA2 gene. This alteration has been identified in several hereditary breast cancer families, and was found to segregate with disease in one family (Menéndez M et al. Breast Cancer Res. Treat., 2012 Apr;132:979-92; Santos C et al. J Mol Diagn, 2014 May;16:324-34; de Juan Jiménez I et al. Fam. Cancer, 2013 Dec;12:767-77). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RT-PCR and minigene analyses determined that this alteration results in the creation of a novel splice acceptor site that causes an out of frame retention of 4 nucleotides of intron 21 (also called intron 22 in the literature) and results in a truncated mRNA transcript (Menéndez M et al. Breast Cancer Res. Treat., 2012 Apr;132:979-92; de Garibay GR et al. Hum. Mutat., 2014 Jan;35:53-7; Santos C et al. J Mol Diagn, 2014 May;16:324-34; Baert A et al. Hum. Mutat. 2018 Apr;39(4):515-526). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985614 SCV001133960 likely pathogenic not provided 2018-10-16 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality (0/276278 chr). Found in at least one symptomatic patient. Predicted to negatively affect a known splice site. Nucleotide conservation is uninformative. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Color Health, Inc RCV000562165 SCV001339848 likely pathogenic Hereditary cancer-predisposing syndrome 2019-06-08 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000985614 SCV001447429 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000985614 SCV000592239 pathogenic not provided no assertion criteria provided clinical testing

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