Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV000805147 | SCV000945092 | pathogenic | Tumor predisposition syndrome 3 | 2023-11-27 | criteria provided, single submitter | clinical testing | This sequence change affects the initiator methionine of the POT1 mRNA. The next in-frame methionine is located at codon 132. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with POT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 650065). This variant at the initiator codon is expected to affect translation initiation. Rescue of translation at the next in-frame methionine at codon 132 is expected to disrupt the oligonucleotide binding 1 (OB1) domain, which facilitates binding to ssDNA critical for POT1 and TPP1 dimerization (PMID: 23502782, 25934589). However, functional studies have not been performed for this specific variant. This variant disrupts a region of the POT1 protein in which other variant(s) (p.Arg117Cys) have been determined to be pathogenic (PMID: 26403419; Invitae). 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. |
Ambry Genetics | RCV003166244 | SCV003854434 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-11-28 | criteria provided, single submitter | clinical testing | The p.M1? variant (also known as c.1A>G) is located in coding exon 1 of the POT1 gene and results from a A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. Sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |