ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.2184+1G>T (rs756363734)

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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 RCV000222999 SCV000277794 likely pathogenic Hereditary cancer-predisposing syndrome 2019-12-18 criteria provided, single submitter clinical testing The c.2184+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 14 of the NBN gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein. As such, this alteration is classified as likely pathogenic.
Counsyl RCV000411514 SCV000486752 likely pathogenic Microcephaly, normal intelligence and immunodeficiency 2016-08-04 criteria provided, single submitter clinical testing
Invitae RCV000411514 SCV000553125 likely pathogenic Microcephaly, normal intelligence and immunodeficiency 2020-07-30 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 14 of the NBN gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with NBN-related conditions. ClinVar contains an entry for this variant (Variation ID: 233424). Donor and acceptor splice site variants 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). 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 RCV000478822 SCV000571724 uncertain significance not provided 2019-12-09 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in an in-frame deletion of a critical region; This variant is associated with the following publications: (PMID: 29922827)
Color Health, Inc RCV000222999 SCV001352703 likely pathogenic Hereditary cancer-predisposing syndrome 2019-05-09 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000411514 SCV001737449 likely pathogenic Microcephaly, normal intelligence and immunodeficiency 2021-05-27 criteria provided, single submitter clinical testing The NBN c.2184+1G>T intronic change results from a a G to T substitution at the +1 position of intron 14 of the NBN gene. This variant is predicted to result in loss of the native splice donor site (PP3) and skipping of exon 14 has been confirmed by RNA studies (PVS1_Strong; internal data). This variant has a maximum subpopulation frequency of 0.012% in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/variant/8-90955480-C-A?dataset=gnomad_r2_1). This variant is absent in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (https://whi.color.com/). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria: PVS1_Strong, PM2_Supporting, PP3.

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