Submissions for variant NM_015450.3(POT1):c.1164-1G>A

gnomAD frequency: 0.00002  dbSNP: rs866612394

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000543378	SCV000655126	pathogenic	Tumor predisposition syndrome 3	2025-01-12	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 13 of the POT1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individual(s) with clinical features of POT1 tumor predisposition syndrome (PMID: 27528712, 29625052). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 475026). Studies have shown that disruption of this splice site results in partial exon deletion, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 27528712; internal data). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001010069	SCV001170214	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-03	criteria provided, single submitter	clinical testing	The c.1164-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 10 of the POT1 gene. In one study, whole exome sequencing performed in familial CLL cases identified c.1164-1G>A in three siblings with CLL; their father with non-Hodgkin's lymphoma was not tested. RNA analysis on the proband with this mutation, also designated as 7:g.124481233C>T, confirmed an abnormal splicing product occurring from an alternative splice acceptor site 43 bp downstream (Speedy HE et al. Blood 2016 11;128:2319-2326). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site; however direct evidence is insufficient at this time (Ambry internal data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Genetic Services Laboratory, University of Chicago	RCV001821623	SCV002065891	likely pathogenic	not provided	2021-11-19	criteria provided, single submitter	clinical testing	DNA sequence analysis of the POT1 gene demonstrated a sequence change in the canonical splice acceptor site in intron 13, c.1164-1G>A. This sequence change has been previously described in three family members with chronic lymphocytic leukemia (PMID: 27528712). Abnormal splicing product was detected by RT-PCR using cDNA from an individual carrying the c.1164-1G>A change (PMID: 27528712). This sequence change has been described in the gnomAD database in one individual which corresponds to a population frequency of 0.0032 % (dbSNP rs866612394). This sequence change is predicted to affect normal splicing of the POT1 gene and result in an abnormal protein. These collective evidences indicate that this sequence change is likely pathogenic.
GeneDx	RCV001821623	SCV002546651	pathogenic	not provided	2024-04-05	criteria provided, single submitter	clinical testing	Canonical splice site variant demonstrated to cause aberrant splicing of exon 14 resulting in a null allele in a gene for which loss of function is a known mechanism of disease (PMID: 27528712); Observed in multiple affected individuals in a familial chronic lymphocytic leukemia kindred, as well as in other individuals with cutaneous melanoma or leukemia in published literature (PMID: 27528712, 29625052, 34193977, 36451132, 36876055); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30877237, 27528712, 29625052, 34218205, 36451132, 34193977, 34482403, 37140166, 36876055)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000543378	SCV005402255	pathogenic	Tumor predisposition syndrome 3	2023-11-29	criteria provided, single submitter	clinical testing	The POT1 c.1164-1G>A intronic change results in a G to A substitution at the -1 position of intron 13 of the POT1 gene and is predicted to disrupt the acceptor splice site. This variant has been reported in individual(s) with familial melanoma (PMID: 36876055). In a large case-control study, this variant was reported in 3 of 2928 individuals with cutaneous melanoma and was not detected in 3298 controls (PMID: 36539277). This variant was also found to co-segregate with chronic lymphocytic leukemia in a family in which three individuals were affected (PMID: 27528712). Finally, it has also been observed in 1 individual with hairy cell leukemia (PMID: 34193977). This variant has a maximum subpopulation frequency of 0.0065% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001821623	SCV005626188	pathogenic	not provided	2024-09-26	criteria provided, single submitter	clinical testing	The POT1 c.1164-1G>A variant disrupts a canonical splice-acceptor site and interferes with normal POT1 mRNA splicing. This variant has been reported in the published literature in individuals with melanoma (PMID: 36876055 (2023), 36539277(2022)), leukemia (PMID: 34482403 (2022), 34193977 (2021), 29625052 (2018), 27528712 (2016)) and unspecified cancer (PMID: 37140166 (2023)). Functional studies demonstrated that this variant was damaging to protein function (PMID: 37140166 (2023), 36539277 (2022), 27528712 (2016)). The frequency of this variant in the general population, 0.000032 (1/31346 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
The Telomere Center at Johns Hopkins, Johns Hopkins University School of Medicine	RCV003329304	SCV003853316	pathogenic	Long telomere syndrome	2022-08-01	no assertion criteria provided	clinical testing
OMIM	RCV000543378	SCV004036159	pathogenic	Tumor predisposition syndrome 3	2023-09-25	no assertion criteria provided	literature only