ClinVar Miner

Submissions for variant NM_002528.7(NTHL1):c.349C>T (p.Pro117Ser)

dbSNP: rs149277519
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000794718 SCV000934143 uncertain significance not provided 2025-01-29 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 125 of the NTHL1 protein (p.Pro125Ser). This variant is present in population databases (rs149277519, gnomAD 0.01%). This missense change has been observed in individual(s) with NTHL1-related cancer (PMID: 33454955). ClinVar contains an entry for this variant (Variation ID: 641473). 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 RCV001021012 SCV001182573 uncertain significance Hereditary cancer-predisposing syndrome 2023-09-14 criteria provided, single submitter clinical testing The p.P125S variant (also known as c.373C>T), located in coding exon 2 of the NTHL1 gene, results from a C to T substitution at nucleotide position 373. The proline at codon 125 is replaced by serine, an amino acid with similar properties. This amino acid position is well 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.
GeneDx RCV000794718 SCV001802088 uncertain significance not provided 2024-11-01 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed reportedly compound heterozygous with a pathogenic NTHL1 variant in a patient with multiple polyps (PMID: 33454955); This variant is associated with the following publications: (PMID: 33454955, 36969007)
Baylor Genetics RCV003472343 SCV004192103 uncertain significance Familial adenomatous polyposis 3 2024-03-24 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004751707 SCV005345024 uncertain significance NTHL1-related disorder 2024-03-29 no assertion criteria provided clinical testing The NTHL1 c.373C>T variant is predicted to result in the amino acid substitution p.Pro125Ser. This variant has been reported in an individual presenting with colorectal cancer or polyposis (Table 2, Boulouard et al. 2021. PubMed ID: 33454955). This variant is reported in 0.014% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/641473/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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