Submissions for variant NM_002528.7(NTHL1):c.488C>T (p.Thr163Met)

gnomAD frequency: 0.00001  dbSNP: rs766136810

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000818852	SCV000959486	uncertain significance	not provided	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 171 of the NTHL1 protein (p.Thr171Met). This variant is present in population databases (rs766136810, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 33980861). ClinVar contains an entry for this variant (Variation ID: 661437). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The methionine 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.
GeneDx	RCV000818852	SCV001790749	uncertain significance	not provided	2019-08-20	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27149842)
Ambry Genetics	RCV002345882	SCV002646549	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-14	criteria provided, single submitter	clinical testing	The p.T171M variant (also known as c.512C>T), located in coding exon 3 of the NTHL1 gene, results from a C to T substitution at nucleotide position 512. The threonine at codon 171 is replaced by methionine, an amino acid with similar properties. This variant has been reported in a patient diagnosed with serrated polyposis syndrome at age 32 with no personal history of cancer. There was a family history of colon cancer on the maternal side of the family (Murphy A et al. J Gastroenterol Hepatol. 2022 May;37:861-869). 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.
Baylor Genetics	RCV003467490	SCV004192101	uncertain significance	Familial adenomatous polyposis 3	2023-10-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000818852	SCV005623921	uncertain significance	not provided	2024-05-03	criteria provided, single submitter	clinical testing	The NTHL1 c.512C>T (p.Thr171Met) variant has been reported in the published literature in individuals affected with serrated polyposis syndrome (PMID: 35128723 (2022)) and breast cancer (PMID: 33980861 (2021)). The frequency of this variant in the general population, 0.000016 (4/247666 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.
Fulgent Genetics, Fulgent Genetics	RCV003467490	SCV005642820	uncertain significance	Familial adenomatous polyposis 3	2024-01-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004751737	SCV005355741	uncertain significance	NTHL1-related disorder	2024-04-11	no assertion criteria provided	clinical testing	The NTHL1 c.512C>T variant is predicted to result in the amino acid substitution p.Thr171Met. This variant has been reported in an individual with a history of breast cancer and an individual with a history of serrated polyposis syndrome (Supplementary Table 2, Li et al. 2021. PubMed ID: 33980861; Table 4, Murphy et al. 2022. PubMed ID: 35128723). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. In ClinVar, this variant is interpreted as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/661437/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.