Total submissions: 13
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000165888 | SCV000216641 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-10-10 | criteria provided, single submitter | clinical testing | The c.37+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 1 of the NBN gene. This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535) and in 1/131 high grade serous ovarian cancer patients from Serbia (Krivokuca A et al. J. Hum. Genet., 2019 Apr;64:281-290). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor 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; however, direct evidence is insufficient at this time (Ambry internal data). As such, this alteration is classified as likely pathogenic. |
Labcorp Genetics |
RCV000470841 | SCV000553112 | likely pathogenic | Microcephaly, normal intelligence and immunodeficiency | 2023-10-04 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 1 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 (rs574673404, gnomAD 0.004%). Disruption of this splice site has been observed in individual(s) with endometrial, breast, and/or ovarian cancer (PMID: 30651582, 34284872, 34994648). ClinVar contains an entry for this variant (Variation ID: 186314). RNA analysis provides insufficient evidence to determine the effect of this variant on NBN splicing (Invitae). 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. |
Counsyl | RCV000470841 | SCV000798225 | likely pathogenic | Microcephaly, normal intelligence and immunodeficiency | 2018-03-01 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000708614 | SCV000821750 | likely pathogenic | not provided | 2020-01-01 | criteria provided, single submitter | clinical testing | This variation occurs 1 base after exon 1 of the NBN gene. This position is highly conserved in the human and other genomes and is crucial in mRNA processing. This mutation is expected to result in incorrect splicing, alteration in the reading frame and a truncated protein. The mutation database ClinVar contains entries for this variant (Variation ID: 186314) |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000470841 | SCV001360493 | likely pathogenic | Microcephaly, normal intelligence and immunodeficiency | 2023-05-12 | criteria provided, single submitter | clinical testing | Variant summary: NBN c.37+1G>A 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: Four predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.2e-06 in 245328 control chromosomes (gnomAD). c.37+1G>A has been reported in the literature in individuals affected with various types of cancer (example: Tsaousis_2019, Levine_2021, Yang_2022 and Krivokuca_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34284872, 34994648, 31159747, 36451132). Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
Department of Molecular Diagnostics, |
RCV001310161 | SCV001499749 | likely pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2020-04-02 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000708614 | SCV001830906 | likely pathogenic | not provided | 2022-07-20 | 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 at significant frequency in large population cohorts (gnomAD); Observed in individuals with ovarian or kidney cancer (Huang 2018, Krivokuca 2019); This variant is associated with the following publications: (PMID: 29625052, 9590180, 16415040, 31159747, 31589614, 32295079, 30651582, 32906206) |
Revvity Omics, |
RCV000708614 | SCV002018222 | pathogenic | not provided | 2019-04-18 | criteria provided, single submitter | clinical testing | |
Sema4, |
RCV000165888 | SCV002536669 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2021-04-11 | criteria provided, single submitter | curation | |
Baylor Genetics | RCV003468760 | SCV004199518 | likely pathogenic | Aplastic anemia | 2024-03-01 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV005042333 | SCV005675577 | likely pathogenic | Microcephaly, normal intelligence and immunodeficiency; Aplastic anemia; Acute lymphoid leukemia | 2024-03-28 | criteria provided, single submitter | clinical testing | |
CZECANCA consortium | RCV001270989 | SCV001451801 | pathogenic | Breast and/or ovarian cancer | 2019-06-11 | no assertion criteria provided | clinical testing | |
Natera, |
RCV000470841 | SCV001461787 | likely pathogenic | Microcephaly, normal intelligence and immunodeficiency | 2020-09-16 | no assertion criteria provided | clinical testing |