Submissions for variant NM_002485.5(NBN):c.1456T>C (p.Ser486Pro)

dbSNP: rs587781380

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129206	SCV000183954	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-07	criteria provided, single submitter	clinical testing	The p.S486P variant (also known as c.1456T>C), located in coding exon 11 of the NBN gene, results from a T to C substitution at nucleotide position 1456. The serine at codon 486 is replaced by proline, an amino acid with similar properties. In one study, this alteration was observed in 1/3236 cases with invasive epithelial ovarian cancer and 0/3431 controls (Ramus SJ et al. J Natl Cancer Inst, 2015 Nov;107:). This variant was also identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). 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.
GeneDx	RCV000486944	SCV000565976	uncertain significance	not provided	2017-12-14	criteria provided, single submitter	clinical testing	This variant is denoted NBN c.1456T>C at the cDNA level, p.Ser486Pro (S486P) at the protein level, and results in the change of a Serine to a Proline (TCT>CCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NBN Ser486Pro was not observed in large population cohorts (Lek 2016). Since Serine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. NBN Ser486Pro is not located in a known functional domain. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether NBN Ser486Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000636744	SCV000758185	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2024-09-03	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 486 of the NBN protein (p.Ser486Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NBN-related conditions. ClinVar contains an entry for this variant (Variation ID: 140934). 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 tolerated. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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.
Genome-Nilou Lab	RCV000636744	SCV002044620	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003398754	SCV004122689	uncertain significance	not specified	2023-10-10	criteria provided, single submitter	clinical testing	Variant summary: NBN c.1456T>C (p.Ser486Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250260 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1456T>C has been reported in the literature in individuals affected with cancer, without strong evidence for causality (Ramus_2015, Belhadj_2023). These reports do not provide unequivocal conclusions about association of the variant with Nijmegen Breakage Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003467105	SCV004199652	uncertain significance	Aplastic anemia	2023-05-28	criteria provided, single submitter	clinical testing