rs947005337

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5

The NM_015450.3(POT1):c.233T>C(p.Ile78Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000871 in 1,607,628 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I78V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

POT1
NM_015450.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:2O:1

Conservation

PhyloP100: 5.99

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 Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a strand (size 11) in uniprot entity POTE1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_015450.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.945

PP5

Variant 7-124870933-A-G is Pathogenic according to our data. Variant chr7-124870933-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 475073.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=3, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POT1	NM_015450.3 linkuse as main transcript	c.233T>C	p.Ile78Thr	missense_variant	7/19	ENST00000357628.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POT1	ENST00000357628.8 linkuse as main transcript	c.233T>C	p.Ile78Thr	missense_variant	7/19	2	NM_015450.3	P1	Q9NUX5-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000162

AC:

AN:

246852

Hom.:

AF XY:

0.00000749

AC XY:

AN XY:

133562

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000303

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000891

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000824

AC:

AN:

1455490

Hom.:

Cov.:

AF XY:

0.00000967

AC XY:

AN XY:

724026

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000232

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000361

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000451

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Tumor predisposition syndrome 3

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 26, 2023	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Center of Human Genetics, Hôpital Erasme	-	The variant is rare in gnomADv4 (14/1607628 alleles ; frequency : 0.00087%). Isoleucine 78 is an amino acid that seems very conserved in evolution except in zebrafish. The variant has been reported in an individual with multiple primary melanomas (PMID: 24686846), in several families with melanoma (PMID: 30586141_2018) and in an individual with 2 melanomas and thyroid cancer (PMID: 30451293_2019). This variant is located in the DNA binding domain of POT1 and was recently shown to impair the ability of POT1 to bind to telomeres (PMID:30586141_2018). The patient's phenotype and family history are compatible with the pathology associated with POT1 gene. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 78 of the POT1 protein (p.Ile78Thr). This variant is present in population databases (no rsID available, gnomAD 0.03%). This missense change has been observed in individuals with clinical features consistent with POT1-related conditions (PMID: 24686846, 30586141, 34193977; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 475073). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POT1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects POT1 function (PMID: 30586141). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 03, 2023	The frequency of this variant in the general population, 0.0003 (3/9890 chromosomes in Ashkenazi Jewish subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in an individual with melanoma (PMID: 30586141 (2018), 30451293 (2018), 24686846 (2014)) and chronic lymphocytic leukemia (PMID: 34193977 (2021)). This variant has also been shown to have a deleterious effect on POT1 protein function (PMID: 30586141 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2023	Published functional studies demonstrate a damaging effect: disrupted telomere binding and telomere elongation (Wong et al., 2019; DeBoy et al., 2023); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with multiple primary melanomas and/or with familial melanoma; however, several unaffected carriers were also identified (Shi et al., 2014; Potrony et al., 2019; DeBoy et al., 2023; Goldstein et al., 2023); Observed in individuals with lymphoid or myeloid malignancies, as well as individuals with thyroid cancer (Lim et al., 2021; DeBoy et al., 2023); This variant is associated with the following publications: (PMID: 24686846, 30451293, 32015491, 31259407, Offin_2020_Abstract, 32155570, 34648949, 32172474, 32987645, 34193977, 36624550, 28393830, 36876055, 37140166, 30586141) -

Long telomere syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

The Telomere Center at Johns Hopkins, Johns Hopkins University School of Medicine

Aug 01, 2022

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2023

The p.I78T variant (also known as c.233T>C), located in coding exon 3 of the POT1 gene, results from a T to C substitution at nucleotide position 233. The isoleucine at codon 78 is replaced by threonine, an amino acid with similar properties. This variant has been reported in at least three unrelated individuals with melanoma without other clear mutations identified (Wong K et al. JAMA Dermatol, 2019 05;155:604-609; Potrony M et al. Br J Dermatol, 2019 07;181:105-113; Goldstein AM et al. JAAD Int, 2023 Jun;11:43-51; Shi J et al. Nat. Genet. 2014 May;46:482-6; DeBoy EA et al. N Engl J Med, 2023 May). This alteration was also identified in an individual diagnosed with CML and a second individual diagnosed with CLL (Lim TL et al. Leukemia, 2022 01;36:283-287). Haplotype analysis performed in unrelated carriers of p.I78T identified a common haplotype, suggestive of a founder event (Wong K et al. JAMA Dermatol, 2019 05;155:604-609). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with POT1-related disease (Ambry internal data). However, this variant has also been identified in individuals without melanoma or other POT1 related tumors (Ambry internal data). Multiple in vitro functional studies indicated that the p.I78T variant was unable to bind telomeres compared to wild type, resulting in elongated telomeres following ectopic expression (Wong K et al. JAMA Dermatol, 2019 05;155:604-609; DeBoy EA et al. N Engl J Med, 2023 May). Direct measurements from patient cells also showed longer telomeres as compared to controls (DeBoy EA et al. N Engl J Med, 2023 May). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 29, 2018

- -

Melanoma, cutaneous malignant, susceptibility to, 1

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

Variant interpreted as Uncertain significance and reported on 03-23-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;D

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.91

D;.

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Uncertain

-0.044

MutationAssessor

Uncertain

2.8

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-4.7

D;D

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;.

Vest4

0.83

MutPred

0.88

Gain of methylation at R80 (P = 0.0588);Gain of methylation at R80 (P = 0.0588);

MVP

0.77

MPC

2.2

ClinPred

0.92

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.86

gMVP

0.95

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