ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.9257-2A>G

dbSNP: rs886040954
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Total submissions: 7
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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 RCV000258310 SCV000328091 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2015-10-02 criteria provided, single submitter clinical testing
Invitae RCV000456394 SCV000549868 pathogenic Hereditary breast ovarian cancer syndrome 2023-07-10 criteria provided, single submitter clinical testing Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This sequence change affects an acceptor splice site in intron 24 of the BRCA2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 267722). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000510064 SCV000608054 likely pathogenic Hereditary cancer-predisposing syndrome 2022-05-24 criteria provided, single submitter clinical testing The c.9257-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 24 in the BRCA2 gene. This nucleotide position is highly conserved in available vertebrate species. This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat. 2018 05;39:593-620). 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; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000456394 SCV000917025 pathogenic Hereditary breast ovarian cancer syndrome 2021-08-09 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9257-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes the canonical 3' splice acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 249820 control chromosomes. c.9257-2A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome as well as prostate cancer (example, Rebbeck_2018, Nyberg_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories and an expert panel (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=3)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health RCV000510064 SCV001344493 likely pathogenic Hereditary cancer-predisposing syndrome 2022-02-18 criteria provided, single submitter clinical testing This variant causes an A to G nucleotide substitution at the -2 position of intron 24 of the BRCA2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has not been reported in individuals affected with hereditary cancer in the literature, but has been identified in in 3 families among the CIMBA participants (PMID: 29446198). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
GeneDx RCV001553412 SCV001774274 pathogenic not provided 2019-10-03 criteria provided, single submitter clinical testing Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); This variant is considered pathogenic by an expert panel (CIMBA); Also known as BRCA2 9485-2A>G; This variant is associated with the following publications: (PMID: 31589614, 31131967)
Baylor Genetics RCV003475884 SCV004210549 pathogenic Familial cancer of breast 2022-06-29 criteria provided, single submitter clinical testing

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