ClinVar Miner

Submissions for variant NM_002528.7(NTHL1):c.188C>T (p.Ser63Leu)

gnomAD frequency: 0.00004  dbSNP: rs746458904
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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 RCV000822625 SCV000963435 uncertain significance not provided 2025-02-04 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 71 of the NTHL1 protein (p.Ser71Leu). This variant is present in population databases (rs746458904, gnomAD 0.008%). This missense change has been observed in individual(s) with breast cancer (PMID: 33980861). ClinVar contains an entry for this variant (Variation ID: 664518). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 RCV001014556 SCV001175277 likely benign Hereditary cancer-predisposing syndrome 2024-03-07 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx RCV000822625 SCV001982114 uncertain significance not provided 2024-09-10 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer, as well as in control group (PMID: 33980861); This variant is associated with the following publications: (PMID: 28098136, 33980861)
Sema4, Sema4 RCV001014556 SCV002528932 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-04 criteria provided, single submitter curation
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000822625 SCV005623910 uncertain significance not provided 2023-11-07 criteria provided, single submitter clinical testing The NTHL1 c.212C>T (p.Ser71Leu) variant has been reported in the published literature in healthy individuals and individuals with breast cancer (PMID: 33980861 (2021)). The frequency of this variant in the general population, 0.00007 (9/128630 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.

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