ClinVar Genomic variation as it relates to human health

PP5, PP1, BS1

Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.

The NTHL1 c.268C>T (p.Gln90Ter) change is a nonsense variant that is predicted to cause premature protein truncation and loss of normal protein function. This variant has been reported as homozygous in individuals across multiple families with colon cancer and/or adenomatous polyposis (PMID: 25938944, 27720914, 30248171, 31645984). It has also been reported as compound heterozygous in an individual with adenocarcinoma of the colon and >30 colorectal adenomas (PMID: 26559593). This variant has a maximum subpopulation frequency of 0.35% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). It is referred to as p.Gln82Ter in the NM_002528 transcript. In summary, this variant meets criteria to be classified as pathogenic.

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27712984, 29105096, 31645984, 18515411, 23852950, 26553438, 25525159, 26427841, 25938944, 26559593, 27713038, 27329137, 28306719, 26431160, 27720914, 29454559, 29909963, 30552997, 29900613, 30753826, 31227763, 31243857, 31285513, 30859360, 30248171, 30267214, 30877237, 31263571, 31980526, 32581362, 33193653, 32860789, 32949222)

This variant causes the premature termination of NTHL1 protein synthesis. In the published literature, this variant has been reported in numerous compound heterozygous and homozygous individuals affected with colorectal cancer, colorectal adenomas, and other neoplasms in the published literature (PMID: 33193653 (2020), 30753826 (2019), 27720914 (2017), 27713038 (2017), 26559593 (2015), 26553438 (2015), 25938944 (2015), 18515411 (2008)). Based on the available information, this variant is classified as pathogenic.

PP1, PP4, PM3, PS4_moderate, PVS1

This sequence change creates a premature translational stop signal (p.Gln90*) in the NTHL1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NTHL1 are known to be pathogenic (PMID: 25938944, 26559593). This variant is present in population databases (rs150766139, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with multiple adenomatous polyps and colorectal cancer (PMID: 25938944, 26559593, 27720914). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 192319). For these reasons, this variant has been classified as Pathogenic.

The p.Q90* pathogenic mutation (also known as c.268C>T), located in coding exon 2 of the NTHL1 gene, results from a C to T substitution at nucleotide position 268. This changes the amino acid from a glutamine to a stop codon within coding exon 2. This mutation has been reported in the homozygous or compound heterozygous state in multiple unrelated individuals with polyposis and/or colorectal cancer (Dallosso AR et al. Gut 2008 Sep;57:1252-5; Weren RD et al. Nat. Genet. 2015 Jun;47:668-71; Kuiper RP et al. Oncotarget 2015 Oct;6:34069-70; Timofeeva MN et al. Sci Rep. 2015 Nov 10;5:16286; Rivera et al. N. Engl. J. Med. 2015 Dec;373:e33; Broderick P et al. Gastroenterology 2017 Jan;152:75-77.e4; Belhadj S et al. Clin. Gastroenterol. Hepatol. 2017 Mar;15:461-462; Whitworth J et al. Am J Hum Genet. 2018 Jul 5;103(1):3-18; Fostira F et al. Clin Genet. 2018 Sep 24). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

ACMG classification criteria: PVS1 very strong, PM3 strong

ACMG criteria used to clasify this variant: PVS1, PS4, PM3_SUP

The NTHL1 c.244C>T variant is classified as Pathogenic (PVS1, PS4_Moderate, PM3_Strong) The NTHL1 c.244C>T variant is a single nucleotide change which is predicted to result in the premature termination of the protein product at codon 82 (PVS1). The variant has been widely reported in the literature in affected patients (PMID:18515411, 25938944, 26431160, 26559593, 27720914, 31285513) (PS4_Moderate). It has been detected as homozygous in 4 unrelated patients and as compound het with another path/likely path variant in 3 patients (eg. PMID:33454955) (PM3_strong). The variant has been reported in dbSNP (rs150766139), in population databases (gnomAD 204/152138 alleles, 0 hom) and as disease causing in the HGMD database (CM088021). It has been reported as Conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 192319). Unaffected heterozygous carriers of this variant have been reported (PMID:18515411, PMID:25938944, PMID:31285513). Note: this variant is also known as (NM_002528.6):c.268C>T; p.Gln90*.

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

NTHL1: PVS1, PP1:Strong

This pathogenic variant is denoted NTHL1 c.268C>T at the cDNA level and p.Gln90Ter (Q90X) (aka: NM_001318193.2:c.244C>T; NP_001305122.2:p.Gln82Ter) at the protein level. The substitution creates a nonsense variant, which changes a Glycine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been observed in several individuals with colorectal cancer and/or adenomas (Dallosso 2008, Rivera 2015, Timofeeva 2015, Weren 2015). Weren et al. (2015) identified NTHL1 Gln90Ter in the homozygous state in 7 individuals from three families with a history of multiple colorectal adenomas and/or colorectal cancer. Additionally, Rivera et al. (2015) identified NTHL1 Gln90Ter in the compound heterozygous state with a canonical splice variant, confirmed to be in trans through familial testing, in an individual with colon cancer, multiple colorectal adenomas, and other neoplasms. Lastly, other studies identified NTHL1 Gln90Ter in the homozygous or compound heterozygous state in several unrelated individuals with colorectal adenomas and colorectal cancer (Chubb 2016, Belhadj 2017, Broderick 2017). Based on currently available information, we consider NTHL1 Gln90Ter to be pathogenic. Of note, NTHL1-Associated Polyposis (NAP) is a recessive condition associated with two pathogenic variants on opposite chromosomes in NTHL1. Although this variant is considered pathogenic, a second pathogenic variant, as would be required for expression of the recessive condition NAP, was not detected in this individual. We cannot exclude the possibility that this patient harbors a second disease-causing NTHL1 pathogenic variant that is undetectable by this test. NTHL1 has only recently been described in association with cancer predisposition and the risks are not well understood. Based on available data, the presence of two pathogenic variants in NTHL1 is indicative of NTHL1-Associated Polyposis (NAP), an autosomal recessive condition that may confer an increased risk for colorectal cancer and polyps. Although the development of colorectal cancer and attenuated polyposis appears to be the predominant feature of NAP, multiple case reports have described individuals with NAP to have developed multiple extracolonic neoplasms, including breast, endometrial, bladder, and skin cancers as well as several benign findings (Rivera 2015, Weren 2015, Belhadj 2017). The National Comprehensive Cancer Network has management guidelines for individuals with two pathogenic variants in NTHL1 (NCCN) (ClinVar- GeneDx; modified)

The NTHL1 c.268C>T variant is predicted to result in premature protein termination (p.Gln90*). This variant has been reported in the homozygous or compound heterozygous state in individuals with multiple colorectal adenomas and an increased susceptibility to colorectal, endometrial, skin, breast and bladder cancer (Rivera et al. 2015. PubMed ID: 26559593; Weren et al. 2015. PubMed ID: 25938944; Belhadj et al. 2017. PubMed ID: 27720914). This variant was found in the homozygous state in seven individuals from three families that had a history of colorectal adenomas and/or colorectal cancer (Weren et al. 2015. PubMed ID: 25938944). Of note, the three affected women in this study all developed endometrial cancer. Functional studies in B-lymphocytes from homozygous carriers indicate that this variant results in nonsense mediated decay and a ten-fold reduction in NTHL1 RNA expression in comparison to controls (Weren et al. 2015. PubMed ID: 25938944). This variant is reported in 0.35% of alleles in individuals of European (Finnish) descent in gnomAD and is interpreted as pathogenic by the vast majority of submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/192319/). Nonsense variants in NTHL1 are expected to be pathogenic. This variant is interpreted as pathogenic for autosomal recessive NTHL1-related cancer predisposition.

Variant reported in multiple Invitae PIN participants. Variant interpreted as Pathogenic and reported most recently on 6/19/2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.