ClinVar Miner

Submissions for variant NM_002528.7(NTHL1):c.577G>A (p.Gly193Ser)

gnomAD frequency: 0.00003  dbSNP: rs200007034
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000817579 SCV000958148 uncertain significance not provided 2025-01-22 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 201 of the NTHL1 protein (p.Gly201Ser). This variant is present in population databases (rs200007034, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with NTHL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 660395). 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. 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.
Ambry Genetics RCV001024816 SCV001186901 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-08 criteria provided, single submitter clinical testing The p.G201S variant (also known as c.601G>A), located in coding exon 4 of the NTHL1 gene, results from a G to A substitution at nucleotide position 601. The glycine at codon 201 is replaced by serine, an amino acid with similar properties. In a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers, this alteration was identified in 1/57 cases and 0/1358 non-cancer control individuals (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). This alteration was also identified in an individual diagnosed with breast cancer (Li N et al. NPJ Breast Cancer, 2021 May;7:52). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000817579 SCV002047242 uncertain significance not provided 2024-11-19 criteria provided, single submitter clinical testing The NTHL1 c.601G>A (p.Gly201Ser) variant (also known as c.577G>A (p.Gly193Ser) in NM_002528.7) has been reported in the published literature in individuals with breast cancer (PMID: 33980861 (2021)) and melanoma (PMID: 29641532 (2018)). The frequency of this variant in the general population, 0.000085 (3/35392 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
GeneDx RCV000817579 SCV002319099 uncertain significance not provided 2022-10-14 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer, melanoma, and other cancers in published literature (Pritchard et al., 2018; Li et al., 2021); This variant is associated with the following publications: (PMID: 29641532, 33980861)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV002268310 SCV002551595 uncertain significance not specified 2025-03-04 criteria provided, single submitter clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV003153862 SCV003842991 uncertain significance Familial adenomatous polyposis 3 2023-01-10 criteria provided, single submitter clinical testing The NTHL1 c.577G>A (p.Gly193Ser) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect of this variant on protein function, but to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with NTHL1-associated polyposis. 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.
Baylor Genetics RCV003153862 SCV004192091 uncertain significance Familial adenomatous polyposis 3 2024-03-09 criteria provided, single submitter clinical testing

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