7-124858989-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_015450.3(POT1):c.670G>A(p.Asp224Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00017 in 1,610,988 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D224G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 1 hom. )

Consequence

POT1
NM_015450.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:7

Conservation

PhyloP100: 6.12

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 Uncertain_significance. Variant got 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.85

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POT1	NM_015450.3 linkuse as main transcript	c.670G>A	p.Asp224Asn	missense_variant	9/19	ENST00000357628.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POT1	ENST00000357628.8 linkuse as main transcript	c.670G>A	p.Asp224Asn	missense_variant	9/19	2	NM_015450.3	P1	Q9NUX5-1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000718

AC:

AN:

250680

Hom.:

AF XY:

0.0000517

AC XY:

AN XY:

135486

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:

0.000159

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000176

AC:

257

AN:

1458886

Hom.:

Cov.:

AF XY:

0.000167

AC XY:

121

AN XY:

725792

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000205

Gnomad4 OTH exome

AF:

0.000465

GnomAD4 genome

AF:

0.000112

AC:

AN:

152102

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000178

Hom.:

Bravo

AF:

0.000110

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 23, 2021	The frequency of this variant in the general population, 0.00016 (20/128806 chromosomes in European (Non-Finnish) 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 individuals/families with melanoma or lymphoma and in their unaffected family members (PMIDs: 24686846 (2014), 27365461 (2016), 29522175 (2017), and 29693246 (2018)). This variant has also been detected in at least one individual with glioblastoma, one individual with lymphocytic leukemia and in individuals with lung adenocarcinoma (PMIDs: 29625052 (2018) and 31919090 (2020)). Functional studies have shown that this variant results in impaired telomeric binding in vitro and increased telomere length and fragility while the telomerase activity remains comparable to wild type and no significant increase in telomere dysfunction-induced damage foci is detected (PMID: 29693246 (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. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	POT1: PM1, PP1, PS3:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with melanoma, chronic lymphocytic leukemia, and glioblastoma (Artomov et al., 2017; Huang et al., 2018; Lim et al., 2021); Co-segregates with melanoma and/or hematologic malignancies in multiple families, but was also present in unaffected individuals (Shi et al., 2014; McMaster et al., 2018; Nathan et al., 2021); Published functional studies demonstrate increased telomere length and fragility, telomerase activity comparable to wild type, no significant increase in telomere dysfunction-induced damage foci, and impaired binding to single stranded telomeric oligonucleotides (McMaster et al., 2018); This variant is associated with the following publications: (PMID: 31919090, 32155570, 24784786, 25431349, 24686849, 27528712, 27365461, 26403419, 24686846, 25244922, 29693246, 29522175, 30556179, 32033110, 32987645, 32191290, 29625052, Szmyd2021, 34193977, 33216348, 28393830, 34218205, 35977101, 36876055, 36656928, 36539277) -

Tumor predisposition syndrome 3

Pathogenic:1Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 224 of the POT1 protein (p.Asp224Asn). This variant is present in population databases (rs202187871, gnomAD 0.01%). This missense change has been observed in individual(s) with cutaneous melanoma, glioblastoma multiforme, and/or Hodgkin lymphoma and other hematologic malignancies (PMID: 24686846, 29625052, 29693246, 33216348). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 139527). 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: 29693246). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 23, 2024	The p.D224N variant (also known as c.670G>A), located in coding exon 5 of the POT1 gene, results from a G to A substitution at nucleotide position 670. The aspartic acid at codon 224 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in multiple melanoma-prone families (Shi J et al. Nat. Genet., 2014 May;46:482-6; Artomov M et al. J. Natl. Cancer Inst., 2017 12;109) and in three siblings and a mother all affected with Hodgkin's lymphoma (McMaster ML et al. Br. J. Haematol., 2018 05;181:372-377). A recent study also identified this variant in a family affected by multiple cancer types, including cutaneous melanoma and hematopoietic syndromes- chronic myeloid leukemia (CML), Hodgkin's lymphoma, follicular lymphoma, and lentigo myeloid leukemia (LMM) (Nathan V. Br J Haematol. 2021 01;192(2):e57-e60). In a functional study, this alteration demonstrated deficient telomere binding in vitro and increased telomere length and fragility compared to wildtype cells (McMaster ML et al. Br. J. Haematol. 2018 05;181:372-377). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Mar 16, 2022	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 18, 2022

DNA sequence analysis of the POT1 gene demonstrated a sequence change, c.670G>A, in exon 9 that results in an amino acid change, p.Asp224Asn. This sequence change has been described in the gnomAD database with a frequency of 0.016% in the non-Finnish European subpopulation (dbSNP rs202187871). This variant has been observed to segregate with melanoma in one family and with Hodgkin lymphoma in another family (PMID: 24686846, 29693246). Functional studies demonstrated that this sequence change affects protein function, leading to telomere lengthening and fragility (PMID: 29693246). The p.Asp224Asn change affects a highly conserved amino acid residue located in a domain of the POT1 protein that is not known to be functional. The p.Asp224Asn substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences, the clinical significance of the p.Asp224Asn change remains unknown at this time. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.17

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.89

D;D;D

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

D;D;.

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.85

D;D;D

MetaSVM

Uncertain

0.17

MutationAssessor

Uncertain

2.7

M;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.1

D;D;.

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.97

MVP

0.83

MPC

2.0

ClinPred

0.82

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.80

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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