Submissions for variant NM_015450.3(POT1):c.1572G>A (p.Trp524Ter)

dbSNP: rs1794703569

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV001822349	SCV002064813	likely pathogenic	not provided	2021-09-29	criteria provided, single submitter	clinical testing	Sequence analysis of the POT1 gene in this individual demonstrated the presence of the c.1572G>A (p.W524*) change. This sequence change results in the creation of a premature stop codon at amino acid position 524, p.W524*. It is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated POT1 protein with potentially abnormal function. This sequence change is absent in the gnomAD population database. The c.1572G>A change does not appear to have been previously described in individuals with POT1-related disorders. However, POT1 truncating variants (including a downstream truncating variant) have been reported in POT1-related disorders (PMID: 25482530, 28853721). Collectively, this evidence suggests c.1572G>A (p.W524*) is likely pathogenic, however functional studies have not been performed to prove this conclusively.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001869745	SCV002129223	pathogenic	Tumor predisposition syndrome 3	2023-06-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that this premature translational stop signal results in skipping of exon 16 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 1337751). This variant has not been reported in the literature in individuals affected with POT1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp524*) in the POT1 gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and may result in an absent or disrupted protein product.
Ambry Genetics	RCV004040993	SCV005026382	pathogenic	Hereditary cancer-predisposing syndrome	2024-02-01	criteria provided, single submitter	clinical testing	The p.W524* pathogenic mutation (also known as c.1572G>A), located in coding exon 12 of the POT1 gene, results from a G to A substitution at nucleotide position 1572. This changes the amino acid from a tryptophan to a stop codon within coding exon 12. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.