Submissions for variant NM_015450.3(POT1):c.1087C>T (p.Arg363Ter)

gnomAD frequency: 0.00004  dbSNP: rs756198077

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000529317	SCV000655119	pathogenic	Tumor predisposition syndrome 3	2023-12-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg363*) in the POT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POT1 are known to be pathogenic (PMID: 32155570). This variant is present in population databases (rs756198077, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with colorectal cancer and/or melanoma (PMID: 27329137, 29036293). This variant is also known as R232X. ClinVar contains an entry for this variant (Variation ID: 475019). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001248813	SCV001250996	pathogenic	not provided	2023-08-28	criteria provided, single submitter	clinical testing	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; Observed in individuals with a personal and/or family history of POT1-related cancers referred for genetic testing at GeneDx and in published literature (Artomov et al., 2017; Goldstein et al., 2017; Lim et al., 2021); Observed in individuals with colorectal cancer (Chubb et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.(R232X); This variant is associated with the following publications: (PMID: 25482530, 29625052, 31919090, 29550946, 32449991, Hana2022[Somatic], 34193977, 29036293, 32987645, 27329137, 27239034, 29522175)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000529317	SCV002032319	likely pathogenic	Tumor predisposition syndrome 3	2021-11-11	criteria provided, single submitter	clinical testing	The POT1 c.1087C>T (p.Arg363Ter) change is a nonsense variant that is predicted to cause protein truncation and loss of normal protein function (PVS1). This variant has a maximum subpopulation frequency of 0.0047% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/7-124482937-G-A). This variant has been reported in individuals with melanoma (PMID: 29036293, 29522175) and oligodendroglioma (PMID: 29625052). It has also been reported in individuals with other cancers including colorectal cancer (PMID: 27329137), infiltrating ductal carcinoma (PMID: 29625052), renal cell carcinoma (PMID: 29625052), hepatocellular carcinoma (PMID: 29625052), prostate adenocarcinoma (PMID: 29625052), and cutaneous T cell lymphoma (PMID: 27239034). Another truncating variant in exon 13 has been reported in individuals with POT1-associated cancers and has been classified as likely pathogenic (PM5_supporting). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria: PVS1, PM5_supporting.
Ambry Genetics	RCV002431704	SCV002726234	pathogenic	Hereditary cancer-predisposing syndrome	2021-01-06	criteria provided, single submitter	clinical testing	The p.R363* pathogenic mutation (also known as c.1087C>T), located in coding exon 9 of the POT1 gene, results from a C to T substitution at nucleotide position 1087. This changes the amino acid from an arginine to a stop codon within coding exon 9. Designated R232X, this mutation has been detected in an individual with cutaneous malignant melanoma (Goldstein AM et al. Hum Mol Genet, 2017 12;26:4886-4895). This mutation has also been detected in 1/1006 early-onset familial colon cancer cases and 0/1609 healthy control individuals (Chubb D et al. Nat Commun, 2016 06;7:11883). In a study of individuals with familial glioma, this alteration was identified in a cohort 6200 unselected, ethnically matched exome-sequenced individuals (Bainbridge MN et al. J Natl Cancer Inst, 2015 Jan;107:384). In another study, this alteration showed significant enrichment in a cancer population (The Cancer Genome Atlas) when compared to a healthy population cohort (ExAC) (Huang KL et al. Cell, 2018 04;173:355-370.e14). 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.
PreventionGenetics, part of Exact Sciences	RCV003419989	SCV004106599	pathogenic	POT1-related condition	2023-02-22	criteria provided, single submitter	clinical testing	The POT1 c.1087C>T variant is predicted to result in premature protein termination (p.Arg363*). This variant has been reported in the heterozygous state in several individuals with various cancers, including melanoma (Goldstein AM et al 2017. PubMed ID: 29036293), cancers of the breast, kidney, liver and brain (Huang KL et al 2018. PubMed ID: 29625052, supp Table 2A), and colorectal cancer (Chubb et al 2016. PubMed ID: 27329137, Table S4). This variant is reported in 0.0047% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-124482937-G-A). It is classified as likely pathogenic and pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/475019/). Nonsense variants in POT1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Genetic Services Laboratory, University of Chicago	RCV001248813	SCV003839911	likely pathogenic	not provided	2022-02-28	no assertion criteria provided	clinical testing	DNA sequence analysis of the POT1 gene demonstrated a sequence change, c.1087C>T, which results in the creation of a premature stop codon at amino acid position 363, p.Arg363. This likely pathogenic sequence change 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 has been described in the gnomAD database with a frequency of 0.0047% in the non-Finnish European subpopulation (dbSNP rs756198077). This likely pathogenic sequence change has previously been described in individuals with a variety of cancers including melanoma, chronic lymphocytic leukemia, oligodendroglioma colorectal cancer, breast cancer, and others (PMID: 34193977, 29036293, 29522175, 27329137, 29625052, 29625052, 29625052, 29625052, 27239034). This sequence change occurs in the OB3 protein domain where other truncating variants have been reported as pathogenic (PMID: 32155570). Based on these evidences, this variant is classified as likely pathogenic.