Submissions for variant NM_002485.5(NBN):c.249G>A (p.Met83Ile)

dbSNP: rs1438838735

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000566420	SCV000662686	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-05	criteria provided, single submitter	clinical testing	The p.M83I variant (also known as c.249G>A), located in coding exon 3 of the NBN gene, results from a G to A substitution at nucleotide position 249. The methionine at codon 83 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is not well 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	RCV000806996	SCV000947021	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2023-08-28	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 83 of the NBN protein (p.Met83Ile). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 480024). 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function.
GeneDx	RCV001770504	SCV002003450	uncertain significance	not provided	2020-10-12	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genome-Nilou Lab	RCV000806996	SCV002045251	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004569118	SCV005056158	uncertain significance	Aplastic anemia	2024-02-03	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000806996	SCV005689429	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2025-01-08	criteria provided, single submitter	clinical testing	The NBN c.249G>A (p.Met83Ile) missense change has a maximum subpopulation frequency of 0.003% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Nijmegen 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.