Submissions for variant NM_002485.5(NBN):c.2215C>G (p.Leu739Val)

gnomAD frequency: 0.00003  dbSNP: rs370058152

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000590749	SCV000211462	uncertain significance	not provided	2023-04-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in a pediatric astrocytoma patient (Wagener et al., 2021); This variant is associated with the following publications: (PMID: 24894818, 33840814)
Ambry Genetics	RCV000160797	SCV000215461	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-24	criteria provided, single submitter	clinical testing	The p.L739V variant (also known as c.2215C>G), located in coding exon 15 of the NBN gene, results from a C to G substitution at nucleotide position 2215. The leucine at codon 739 is replaced by valine, an amino acid with highly similar properties. This variant was detected in 1/160 children with newly diagnosed cancer. This patient was diagnosed with pilocytic astrocytoma (Wagener R et al. Eur J Hum Genet, 2021 Aug;29:1301-1311). This variant was also reported in 3/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168129	SCV000218788	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 739 of the NBN protein (p.Leu739Val). This variant is present in population databases (rs370058152, gnomAD 0.006%). This missense change has been observed in individual(s) with Hodgkin's lymphoma (PMID: 33840814). ClinVar contains an entry for this variant (Variation ID: 182730). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590749	SCV000697964	uncertain significance	not provided	2016-02-01	criteria provided, single submitter	clinical testing	Variant summary: The c.2215C>G variant affects a conserved nucleotide, resulting in amino acid change from Leu to Val. 2/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). 4/5 programs in Alamut predict that this variant does not affect normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions are not confirmed by experimental studies. This variant is found in 3/115508 control chromosomes at a frequency of 0.000026, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0025). In addition, multiple clinical laboratories classified this variant as VUS. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Mendelics	RCV000168129	SCV000838295	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2018-07-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764782	SCV000895926	uncertain significance	Microcephaly, normal intelligence and immunodeficiency; Aplastic anemia; Acute lymphoid leukemia	2021-11-29	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000590749	SCV002010438	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000168129	SCV002046027	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000160797	SCV002536646	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-25	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000168129	SCV004031232	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2023-07-18	criteria provided, single submitter	clinical testing	The NBN c.2215C>G (p.Leu739Val) missense change has a maximum subpopulation frequency of 0.0062% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in a large case-control study of breast cancer in 3 of 60,466 cases and 2 of 53,461 controls (PMID: 33471991). This variant has been reported in two siblings who developed pilocytic astrocytoma and Hodgkin lymphoma at ten years and eighteen years of age, respectively. Four individuals with this variant is reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with Nijmegan breakage syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Baylor Genetics	RCV004567222	SCV005056157	uncertain significance	Aplastic anemia	2024-02-06	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000168129	SCV002078498	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2020-02-21	no assertion criteria provided	clinical testing