ClinVar Miner

Submissions for variant NM_002485.5(NBN):c.680T>C (p.Phe227Ser)

dbSNP: rs749025721
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478980 SCV000567416 uncertain significance not provided 2015-07-22 criteria provided, single submitter clinical testing This variant is denoted NBN c.680T>C at the cDNA level, p.Phe227Ser (F227S) at the protein level, and results in the change of a Phenylalanine to a Serine (TTT>TCT). This variant was observed in a cohort of individuals referred for hereditary cancer testing (Yorczyk 2014). NBN Phe227Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Phenylalanine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. NBN Phe227Ser occurs at a position that is conserved across species and is located in the region of interaction with MTOR, MAPKAP1 and RICTOR and the region that mediates interaction with SP100 (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether NBN Phe227Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV000548804 SCV000634322 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2022-03-08 criteria provided, single submitter clinical testing 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. This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 227 of the NBN protein (p.Phe227Ser). This variant is present in population databases (rs749025721, gnomAD 0.0009%). 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: 419540). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0").
Genome-Nilou Lab RCV000548804 SCV002044816 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2021-11-07 criteria provided, single submitter clinical testing

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