chr7-124870933-A-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PP3_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:9U:1O:1

Conservation

PhyloP100: 5.99

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 8
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
tumor predisposition syndrome 3
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
glioma susceptibility 9
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
thyroid gland carcinoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
cerebroretinal microangiopathy with calcifications and cysts 3
Inheritance: AR Classification: LIMITED Submitted by: G2P, Ambry Genetics

POT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

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 VariationId is 475073.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015450.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
POT1	NM_015450.3	MANE Select	c.233T>C	p.Ile78Thr	missense	Exon 7 of 19	NP_056265.2
POT1	NR_003102.2		n.676T>C		non_coding_transcript_exon	Exon 7 of 20
POT1	NR_003103.2		n.676T>C		non_coding_transcript_exon	Exon 7 of 18

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
POT1	ENST00000357628.8	TSL:2 MANE Select	c.233T>C	p.Ile78Thr	missense	Exon 7 of 19	ENSP00000350249.3
POT1	ENST00000607932.5	TSL:1	n.233T>C		non_coding_transcript_exon	Exon 3 of 14	ENSP00000476506.1
POT1	ENST00000608057.5	TSL:1	n.233T>C		non_coding_transcript_exon	Exon 3 of 16	ENSP00000476371.1

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

GnomAD2 exomes

AF:

0.0000162

AC:

AN:

246852

AF XY:

0.00000749

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 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

African (AFR)

AF:

0.00

AC:

AN:

33210

American (AMR)

AF:

0.00

AC:

AN:

44076

Ashkenazi Jewish (ASJ)

AF:

0.000232

AC:

AN:

25892

East Asian (EAS)

AF:

0.00

AC:

AN:

39392

South Asian (SAS)

AF:

0.00

AC:

AN:

85168

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53186

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.00000361

AC:

AN:

1108800

Other (OTH)

AF:

0.0000333

AC:

AN:

60046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67964

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000451

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Tumor predisposition syndrome 3

Pathogenic:4

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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, 37466057, 38540414; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 475073). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.

Sep 26, 2023

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Center of Human Genetics, Hôpital Erasme

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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.

May 21, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Pathogenic:3

Dec 15, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The POT1 c.233T>C (p.Ile78Thr) variant has been reported in the published literature in individuals with melanoma (PMID: 37140166 (2023), 36876055 (2023), 30586141 (2019), 30451293 (2019), 24686846 (2014)). This variant has also been identified in an individual with chronic lymphocytic leukemia (PMID: 34193977 (2021)). In addition, this variant has been shown to have a deleterious effect on POT1 protein function (PMID: 37140166 (2023), 30586141 (2019)). The frequency of this variant in the general population, 0.000016 (4/246852 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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, this variant is classified as likely pathogenic.

Dec 08, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in individuals with multiple primary melanomas and/or with familial melanoma; however, several unaffected carriers were also identified (PMID: 24686846, 30451293, 37140166, 36876055); Observed in individuals with lymphoid or myeloid malignancies, as well as individuals with thyroid cancer (PMID: 34193977, 37140166); Published functional studies demonstrate a damaging effect: disrupted telomere binding and telomere elongation (PMID: 37140166, 30586141); 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; 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)

Aug 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

POT1: PM2, PS3:Moderate, PS4:Moderate

Long telomere syndrome

Pathogenic:1

Aug 01, 2022

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

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Hereditary cancer-predisposing syndrome

Pathogenic:1

Jul 06, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 alteration has been observed in multiple individuals with a personal and/or family history that is consistent with POT1-related disease (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; Abu Shtaya A et al. Genes (Basel), 2024 Mar;15; Ambry internal data). However, this variant has also been identified in individuals without melanoma or other POT1 related tumors (Ambry internal data). 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). 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 supporting evidence, this variant is interpreted as a disease-causing mutation.

not specified

Uncertain:1

Mar 29, 2018

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Melanoma, cutaneous malignant, susceptibility to, 1

Other:1

GenomeConnect - Invitae Patient Insights Network

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

-0.044

MutationAssessor

Uncertain

2.8

PhyloP100

6.0

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-4.7

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.83

MutPred

0.88

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

Mutation Taster

=24/76

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over