Submissions for variant NM_002485.5(NBN):c.1142del (p.Pro381fs)

dbSNP: rs587781969

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130355	SCV000185206	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-15	criteria provided, single submitter	clinical testing	The c.1142delC pathogenic mutation, located in coding exon 10 of the NBN gene, results from a deletion of one nucleotide at nucleotide position 1142, causing a translational frameshift with a predicted alternate stop codon (p.P381Qfs*23). This alteration has been described in conjunction with a pathogenic founder mutation in at least one patient with Nijmegen breakage syndrome (Varon R et al. Cell. 1998 May;93:467-76). This alteration has also been reported in cohorts of patients with a personal and/or family history of breast and/or ovarian cancers (Walsh T et al. Proc. Natl. Acad. Sci. USA. 2011 Nov;108:18032-7; Castéra L et al. Eur. J. Hum. Genet. 2014 Nov;22:1305-13; Desmond A et al. JAMA Oncol. 2015 Oct;1:943-51; Lu C et al. Nat Commun. 2015 Dec 22;6:10086; Carter NJ et al. Gynecol Oncol. 2018 12;151:481-488). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000220768	SCV000279248	pathogenic	not provided	2023-11-14	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed with a pathogenic founder variant in individuals with Nijmegen breakage syndrome in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (PMID: 12621246, 9590180); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27038244, 22006311, 10799436, 24549055, 18593981, 26315354, 26270727, 15578693, 16033915, 10792024, 24072268, 28152038, 30322717, 30612635, 26689913, 33439686, 31589614, 29625052, 12621246, 9590180, 28888541, 29922827, 33804961, 36003761, 32191290, 34887416, 36451132)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000007358	SCV000287446	pathogenic	Microcephaly, normal intelligence and immunodeficiency	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro381Glnfs*23) in the NBN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NBN are known to be pathogenic (PMID: 9590180, 16415040). This variant is present in population databases (rs587781969, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with Nijmegen breakage syndrome (PMID: 9590180, 10799436, 12621246, 22006311, 24549055, 26315354). ClinVar contains an entry for this variant (Variation ID: 141731). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000220768	SCV000609313	pathogenic	not provided	2023-01-01	criteria provided, single submitter	clinical testing	NBN: PVS1, PM2
Counsyl	RCV000007358	SCV000678049	likely pathogenic	Microcephaly, normal intelligence and immunodeficiency	2017-05-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000220768	SCV000889542	pathogenic	not provided	2017-10-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007358	SCV001337953	pathogenic	Microcephaly, normal intelligence and immunodeficiency	2020-01-14	criteria provided, single submitter	clinical testing	Variant summary: NBN c.1142delC (p.Pro381GlnfsX23) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.4e-05 in 249986 control chromosomes (gnomAD). c.1142delC has been reported in the literature in multiple individuals affected with Nijmegen Breakage Syndrome (e.g. Bakshi_2003, Varon_1998) as well as in breast and/or ovarian cancer patients (Ramus_2015, Walsh_2011, Carter_2018). These data indicate that the variant is very likely to be associated with disease. No Nibrin protein expression was detected in a cell line derived from a compound heterozygous patient who harbored this variant and another truncating variant (Bakshi_2003). Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000007358	SCV002045343	pathogenic	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000007358	SCV003928054	pathogenic	Microcephaly, normal intelligence and immunodeficiency	2023-03-21	criteria provided, single submitter	clinical testing	The NBN c.1142del (p.Pro381GlnfsTer23) change deletes one nucleotide and causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay. This variant has a maximum subpopulation frequency of 0.0053% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant has been reported as compound heterozygous in an individuals affected with Nijmegen breakage syndrome (PMID: 9590180, 12621246). In addition, this variant has been identified in individuals with ovarian cancer (PMID: 22006311, 26315354, 29625052, 30322717). Two individuals with this variant are reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com/). In summary, this variant meets criteria to be classified as pathogenic.
Baylor Genetics	RCV003467143	SCV004199485	pathogenic	Aplastic anemia	2024-03-24	criteria provided, single submitter	clinical testing
OMIM	RCV000007358	SCV000027557	pathogenic	Microcephaly, normal intelligence and immunodeficiency	1998-05-01	no assertion criteria provided	literature only
GeneReviews	RCV000007358	SCV000494637	not provided	Microcephaly, normal intelligence and immunodeficiency		no assertion provided	literature only
Natera, Inc.	RCV000007358	SCV001460720	pathogenic	Microcephaly, normal intelligence and immunodeficiency	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004745208	SCV005361301	pathogenic	NBN-related disorder	2024-07-29	no assertion criteria provided	clinical testing	The NBN c.1142delC variant is predicted to result in a frameshift and premature protein termination (p.Pro381Glnfs*23). This variant has been observed in the compound heterozygous state in an individual with Nijmegen breakage syndrome (Varon et al. 1998. PubMed ID: 9590180), it has also been observed in the heterozygous state in multiple individuals with breast and/or ovarian cancer (Table 2, Walsh et al. 2011. PubMed ID: 22006311; Table 2, Ramus et al. 2015. PubMed ID: 26315354; Table 4, Castéra et al. 2014. PubMed ID: 24549055; Table 2, Megid et al. 2022. PubMed ID: 36003761; Table 4e, Desmond et al. 2015. PubMed ID: 26270727) and in several individuals with genitourinary cancers (Table 6A, Yang et al. 2022. PubMed ID: 36451132; Table S2, Nguyen-Dumont et al. 2021. PubMed ID: 33804961). This variant is reported in 0.0053% of alleles in individuals of European (non-Finnish) descent in gnomAD and is interpreted as Pathogenic/Likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141731/). Frameshift variants in NBN are expected to be pathogenic. This variant is interpreted as pathogenic.