rs756198077

Positions:

chr7-124842883-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_015450.3(POT1):c.1087C>T(p.Arg363Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000286 in 1,610,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

POT1
NM_015450.3 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 3.57

Variant links:

Genes affected

POT1 (HGNC:17284): (protection of telomeres 1) This gene is a member of the telombin family and encodes a nuclear protein involved in telomere maintenance. Specifically, this protein functions as a member of a multi-protein complex that binds to the TTAGGG repeats of telomeres, regulating telomere length and protecting chromosome ends from illegitimate recombination, catastrophic chromosome instability, and abnormal chromosome segregation. Increased transcriptional expression of this gene is associated with stomach carcinogenesis and its progression. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2008]

POT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 7-124842883-G-A is Pathogenic according to our data. Variant chr7-124842883-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 475019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POT1	NM_015450.3 linkuse as main transcript	c.1087C>T	p.Arg363Ter	stop_gained	13/19	ENST00000357628.8	NP_056265.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POT1	ENST00000357628.8 linkuse as main transcript	c.1087C>T	p.Arg363Ter	stop_gained	13/19	2	NM_015450.3	ENSP00000350249	P1	Q9NUX5-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151996

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000589

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000241

AC:

AN:

248672

Hom.:

AF XY:

0.0000297

AC XY:

AN XY:

134470

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000531

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000281

AC:

AN:

1458678

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

725666

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000351

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000306

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151996

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74246

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000589

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000579

Hom.:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 28, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2023	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) -

Tumor predisposition syndrome 3

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Nov 11, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 24, 2023	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. -

POT1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 2023

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. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.80

MutationTaster

Benign

1.0

A;A

Vest4

0.98

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over