ClinVar Miner

Submissions for variant NM_002485.5(NBN):c.995-2A>G

dbSNP: rs876659521
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000223218 SCV000276088 likely pathogenic Hereditary cancer-predisposing syndrome 2024-01-10 criteria provided, single submitter clinical testing The c.995-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 9 in the NBN gene. In one study, this alteration was observed in 1/3236 cases with invasive epithelial ovarian cancer and 0/3431 controls (Ramus SJ et al. J. Natl. Cancer Inst., 2015 Nov;107). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly 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. 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000231563 SCV000287490 likely pathogenic Microcephaly, normal intelligence and immunodeficiency 2024-07-23 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 8 of the NBN 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 NBN are known to be pathogenic (PMID: 9590180, 16415040). This variant is present in population databases (no rsID available, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with ovarian cancer or clinical features of Nijmegen breakage syndrome (PMID: 26315354, 36964972). ClinVar contains an entry for this variant (Variation ID: 232050). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx RCV000481197 SCV000565310 pathogenic not provided 2021-11-11 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek 2016); Observed in the heterozygous state in individuals with a personal history ovarian cancer (Ramus 2015); This variant is associated with the following publications: (PMID: 26315354)
Counsyl RCV000231563 SCV000790071 likely pathogenic Microcephaly, normal intelligence and immunodeficiency 2017-03-03 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000231563 SCV002045346 pathogenic Microcephaly, normal intelligence and immunodeficiency 2021-11-07 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003407753 SCV004106381 likely pathogenic NBN-related disorder 2023-03-02 criteria provided, single submitter clinical testing The NBN c.995-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant was reported in an individual with ovarian cancer (Ramus et al. 2015. PubMed ID: 26315354, supplementary data). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-90971084-T-C). Variants that disrupt the consensus splice acceptor site in NBN are expected to be pathogenic. This variant is interpreted as likely pathogenic.
Baylor Genetics RCV003475021 SCV004199691 pathogenic Aplastic anemia 2023-03-03 criteria provided, single submitter clinical testing

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