ClinVar Genomic variation as it relates to human health

Variant summary: NBN c.683T>G (p.Ile228Arg) results in a non-conservative amino acid change located in the Nibrin, second BRCT domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.5e-05 in 276394 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome (6.5e-05 vs 0.0025), allowing no conclusion about variant significance. The variant, c.683T>G, has been reported in the literature in an individual being tested for Lynch Syndrome (Yurgelun_2015). These report does 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

The p.I228R variant (also known as c.683T>G), located in coding exon 6 of the NBN gene, results from a T to G substitution at nucleotide position 683. The isoleucine at codon 228 is replaced by arginine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

The NBN c.683T>G, p.(Ile228Arg) variant (rs777460725), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 186350). This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.007 percent (identified on 20 out of 281,876 chromosomes). The isoleucine at position 228 is weakly conserved and computational analyses of the effects of the p.(Ile228Arg) variant on protein structure and function is deleterious (SIFT: damaging, PolyPhen-2: possibly damaging). Altogether, there is not enough evidence to classify the p.(Ile228Arg) variant with certainty.

This sequence change replaces isoleucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 228 of the NBN protein (p.Ile228Arg). This variant is present in population databases (rs777460725, gnomAD 0.01%). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 25980754). This missense change has been observed to co-occur in individuals with a different variant in NBN that has been determined to be pathogenic (Invitae), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 186350). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate loss of protein stability and sensitivity to mitomycin-C similar to a positive control (PMID: 37503171); Observed in individuals with breast cancer, Lynch-syndrome associated cancer and/or polyps, or B-cell acute lymphoblastic leukemia (PMID: 33471991, 25980754, 37503171); This variant is associated with the following publications: (PMID: 33471991, 25980754, 24894818, 37503171, 36346689, 38446568)

The NBN c.683T>G variant is predicted to result in the amino acid substitution p.Ile228Arg. This variant has been reported as a variant of uncertain significance in an individual undergoing testing for Lynch syndrome (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754). This variant has also been reported as a variant of uncertain significance in a study of NBN as a pan-cancer susceptibility gene (Table S2, Belhadj et al. 2023. PubMed ID: 36346689). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted as a variant of uncertain significance in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/186350/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.