ClinVar Genomic variation as it relates to human health

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3.

In the published literature, this variant has been reported in individuals with colorectal cancer and polyposis (PMID: 31285513 (2019)) and breast cancer (PMID: 33980861 (2021)). An experimental study reports this variant has neutral effect on NTHL1 DNA damage repair activity (PMID: 30552997 (2019)). The frequency of this variant in the general population, 0.000047 (6/126892 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on NTHL1 mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites . Based on the available information, we are unable to determine the clinical significance of this variant.

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 286 of the NTHL1 protein (p.Gly286Ser). This variant is present in population databases (rs139309757, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer and/or polyposis and colorectal cancer (PMID: 31285513, 33980861). ClinVar contains an entry for this variant (Variation ID: 587358). 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. Experimental studies have shown that this missense change does not substantially affect NTHL1 function (PMID: 30552997). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.

The p.G286S variant (also known as c.856G>A), located in coding exon 6 of the NTHL1 gene, results from a G to A substitution at nucleotide position 856. The glycine at codon 286 is replaced by serine, an amino acid with similar properties. This variant was detected in the heterozygous state in one individual diagnosed with attenuated adenomatous polyposis (Lorca V et al. Sci Rep. 2019 Jul;9:9814). This alteration has been reported in 1/4985 breast cancer cases and 0/4786 cancer-free controls (Li N et al. NPJ Breast Cancer, 2021 May;7:52). In one functional study the p.G286S variant exhibited expression levels and DNA cleavage activity similar to wild-type indicating that it did not lead to defective repair activity (Shinmura K et al. Free Radic. Biol. Med. 2019 02;131:264-273). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate no damaging effect: DNA glycosylase activity comparable to wild type (PMID: 30552997); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31285513, 30552997, 33980861)