Submissions for variant NM_002485.5(NBN):c.156_157del (p.Ser53fs)

dbSNP: rs767454740

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000410370	SCV000486614	likely pathogenic	Microcephaly, normal intelligence and immunodeficiency	2016-07-07	criteria provided, single submitter	clinical testing
Invitae	RCV000410370	SCV000553052	pathogenic	Microcephaly, normal intelligence and immunodeficiency	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser53Cysfs*9) 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 (rs767454740, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 24549055). ClinVar contains an entry for this variant (Variation ID: 371121). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000484600	SCV000568560	likely pathogenic	not provided	2021-10-26	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 a significant frequency in large population cohorts (Lek 2016); Observed in an individual with a personal and/or family history of breast and/or ovarian cancer (Castera 2014); This variant is associated with the following publications: (PMID: 29922827, 24549055, 31263571)
Genetic Services Laboratory, University of Chicago	RCV000502852	SCV000595917	likely pathogenic	Acute lymphoid leukemia	2016-09-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587195	SCV000697948	likely pathogenic	Hereditary breast ovarian cancer syndrome	2016-04-11	criteria provided, single submitter	clinical testing	Variant summary: The variant of interest causes a frameshift mutation resulting in a predicted truncated NBN protein, a mechanism for disease. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/121384, which does not exceed the predicted maximum expected allele frequency for a pathogenic NBN variant of 1/8000 for HBOC. The variant of interest has been reported in an affected individual via a publication that consisted of a cohort of HBOC individuals. The variant of interest has not been reported in clinical laboratories or databases. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Likely Pathogenic.
Mendelics	RCV000410370	SCV000838320	pathogenic	Microcephaly, normal intelligence and immunodeficiency	2018-07-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000584632	SCV001172585	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-28	criteria provided, single submitter	clinical testing	The c.156_157delTT pathogenic mutation, located in coding exon 2 of the NBN gene, results from a deletion of two nucleotides between nucleotide positions 156 and 157, causing a translational frameshift with a predicted alternate stop codon (p.S53Cfs*9). This deletion has been reported in one high risk breast and/or ovarian cancer individual (Castéra L et al. Eur. J. Hum. Genet. 2014 Nov;22:1305-13). (Hu C et al. JAMA, 2018 06;319:2401-2409). (Byrjalsen A et al. PLoS Genet, 2020 12;16:e1009231). (Zuntini R et al. Int J Mol Sci, 2021 May;22:). 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.
Genome-Nilou Lab	RCV000410370	SCV002045379	pathogenic	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484600	SCV002046233	pathogenic	not provided	2020-09-18	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of NBN protein synthesis. It has been reported in individuals affected with hereditary breast and/or ovarian cancer in the published literature (PMID: 24549055 (2014)). Therefore, the variant is classified as pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252110	SCV002522770	pathogenic	See cases	2021-06-26	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1, PS4, PM2
Fulgent Genetics, Fulgent Genetics	RCV002502428	SCV002810496	pathogenic	Microcephaly, normal intelligence and immunodeficiency; Aplastic anemia; Acute lymphoid leukemia	2022-03-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003470344	SCV004199597	pathogenic	Aplastic anemia	2023-08-23	criteria provided, single submitter	clinical testing