ClinVar Miner

Submissions for variant NM_002528.7(NTHL1):c.675_676del (p.Ser226fs)

dbSNP: rs1567369247
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002005756 SCV002273822 pathogenic not provided 2024-11-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser234Argfs*38) in the NTHL1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 79 amino acid(s) of the NTHL1 protein. This variant is present in population databases (no rsID available, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with colorectal cancer (PMID: 33260537). This variant disrupts a region of the NTHL1 protein in which other variant(s) (p.Gln287*) have been determined to be pathogenic (PMID: 27329137, 28912133, 30753826; internal data). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc. RCV004591684 SCV005082393 pathogenic Familial adenomatous polyposis 3 2024-04-24 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Ambry Genetics RCV004945862 SCV005460408 pathogenic Hereditary cancer-predisposing syndrome 2024-07-24 criteria provided, single submitter clinical testing The c.699_700delGT pathogenic mutation, located in coding exon 4 of the NTHL1 gene, results from a deletion of two nucleotides at nucleotide positions 699 to 700, causing a translational frameshift with a predicted alternate stop codon (p.S234Rfs*38). This alteration occurs at the 3' terminus of NTHL1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 25% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected and the impacted region is critical for protein function (Ambry internal data). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.

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