Submissions for variant NM_002485.5(NBN):c.37+1G>A

gnomAD frequency: 0.00002  dbSNP: rs574673404

Total submissions: 12

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 (formerly Invitae), Labcorp	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
GeneKor MSA	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, LabCorp	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, Institute of Oncology Ljubljana	RCV001310161	SCV001499749	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-04-02	criteria provided, single submitter	clinical testing
GeneDx	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, Revvity	RCV000708614	SCV002018222	pathogenic	not provided	2019-04-18	criteria provided, single submitter	clinical testing
Sema4, 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
CZECANCA consortium	RCV001270989	SCV001451801	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000470841	SCV001461787	likely pathogenic	Microcephaly, normal intelligence and immunodeficiency	2020-09-16	no assertion criteria provided	clinical testing