Submissions for variant NM_002485.5(NBN):c.698_701del (p.Lys233fs)

dbSNP: rs587780100

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212735	SCV000149713	pathogenic	not provided	2023-09-27	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; Not observed at significant frequency in large population cohorts (gnomAD); Also known as NBS1 698del4; This variant is associated with the following publications: (PMID: 9590180, 26681312, 24072268, 29915322, 31948886, 26315354, 26534844, 23149842, 27038244, 28374160, 28152038, 30043523, 29961768, 29625052, 26689913, 35626031, 34326862, 33804961, 32427313, 29922827, 32885271, 32338768, 28888541, 36451132, 36623239, 15474156)
Ambry Genetics	RCV000115804	SCV000213967	pathogenic	Hereditary cancer-predisposing syndrome	2024-07-05	criteria provided, single submitter	clinical testing	The c.698_701delAACA pathogenic mutation, located in coding exon 6 of the NBN gene, results from a deletion of 4 nucleotides at nucleotide positions 698 to 701, causing a translational frameshift with a predicted alternate stop codon (p.K233Sfs*5). This alteration was detected in a series of individuals with Nijmegen breakage syndrome (NBS) (Varon R et al. Cell. 1998 May;93:467-76). This alteration has also been reported in a woman with bilateral breast cancer, multiple skin cancers, and a family history of cancer and a male patient with prostate cancer (Gass J et al. Fam. Cancer. 2017 Oct;16:551-553; Wu Y et al. Eur Urol Oncol. 2020 Apr;3(2):224-230). 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.
Genetic Services Laboratory, University of Chicago	RCV000193543	SCV000248142	pathogenic	Microcephaly, normal intelligence and immunodeficiency	2015-03-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000193543	SCV000261243	pathogenic	Microcephaly, normal intelligence and immunodeficiency	2024-12-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys233Serfs*5) 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 (rs587780100, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with Nijmegen breakage syndrome (NBS), and breast/ovarian cancer (PMID: 9590180, 15474156, 26315354, 26534844). This variant is also known as 698del4. ClinVar contains an entry for this variant (Variation ID: 127878). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212735	SCV000889556	pathogenic	not provided	2024-05-10	criteria provided, single submitter	clinical testing	The NBN c.698_701del (p.Lys233Serfs*5) variant alters the translational reading frame of the NBN mRNA and causes the premature termination of NBN protein synthesis. This variant has been reported in the published literature in reported in the biallelic state in multiple individuals with Nijmegen breakage syndrome (PMID 9590180 (1998), 10799436 (2000), 15474156 (2004)), as well as in the heterozygous state in multiple individuals with prostate cancer (PMID: 29915322 (2018)), pancreatic cancer (PMID: 29961768 (2019)), lung cancer (PMID: 26681312 (2015)), ovarian cancer (PMID: 26315354 (2015), PMID: 28888541 (2017)), and breast cancer and skin cancers (PMID: 28374160 (2017), 30043523 (2018)). The frequency of this variant in the general population, 0.000065 (2/30740 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000193543	SCV000917863	pathogenic	Microcephaly, normal intelligence and immunodeficiency	2018-08-03	criteria provided, single submitter	clinical testing	Variant summary: NBN c.698_701delAACA (p.Lys233SerfsX5) 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 2e-05 in 252006 control chromosomes (gnomAD). The variant, c.698_701delAACA, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer and Nijmegen Breakage Syndrome (Varon_1998, Gass_2017, Ramus_2015, Li_2015, Susswein_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000193543	SCV002045359	pathogenic	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498497	SCV002813890	pathogenic	Microcephaly, normal intelligence and immunodeficiency; Aplastic anemia; Acute lymphoid leukemia	2024-02-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467062	SCV004199511	pathogenic	Aplastic anemia	2024-03-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000212735	SCV005041192	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	NBN: PVS1, PS4:Moderate, PM2:Supporting
OMIM	RCV000193543	SCV000027554	pathogenic	Microcephaly, normal intelligence and immunodeficiency	1998-05-01	no assertion criteria provided	literature only
GeneReviews	RCV000193543	SCV000494629	not provided	Microcephaly, normal intelligence and immunodeficiency		no assertion provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354502	SCV001549137	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The NBN p.Lys233SerfsX5 variant was identified in 2 of 7792 proband chromosomes (frequency: 0.00026) from individuals or families with hereditary breast and ovarian cancer (Li_2015, Ramus_2015). The variant was also identified in dbSNP (ID: rs587780100) as “With Pathogenic allele”, ClinVar (as pathogenic by GeneDx, Ambry Genetics, University of Chicago, Invitae, Color Genomics, OMIM and GeneReviews), Clinvitae (3x as in ClinVar), LOVD 3.0, and Zhejiang Colon Cancer Database. The variant was not identified in Cosmic database. The variant was identified in control databases in 5 of 245144 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 15226 chromosomes (freq: 0.000066), European (Non-Finnish) in 4 of 111062 chromosomes (freq: 0.000036), but it was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), Latino, Other, and South Asian populations. The variant has been reported in families with Nijmegen Breakage Syndrome as well as in individuals with hereditary breast and ovarian cancer (HBOC), and is reported as a variant of English origin (Cybulski_2013, Meyer_2004, Varon_1998). The p.Lys233SerfsX5 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 233 and leads to a premature stop codon at position 237. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the NBN gene are an established mechanism of disease in HBOC and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Natera, Inc.	RCV000193543	SCV002078638	pathogenic	Microcephaly, normal intelligence and immunodeficiency	2020-11-02	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004745189	SCV005359400	pathogenic	NBN-related disorder	2024-09-13	no assertion criteria provided	clinical testing	The NBN c.698_701delAACA variant is predicted to result in a frameshift and premature protein termination (p.Lys233Serfs*5). This variant has been reported in a patient with Nijmemgen breakage syndrome (Varon et al. 1998. PubMed ID: 9590180) and in individuals with various cancers, including breast and skin, prostate, or ovarian cancers (for example, Gass et al. 2017. PubMed ID: 28374160; Supplementary Table, Lerner-Ellis. 2020. PubMed ID: 32885271; Table S7, Lilyquist. 2017. PubMed ID: 28888541). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD, and has been interpreted as pathogenic in ClinVar. Frameshift variants in NBN are expected to be pathogenic. This variant is interpreted as pathogenic.