rs780936436

Variant names:

• chr7-124863547-G-A
• rs780936436
• NM_015450.3:c.349C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-124863547-G-A
• chr7-124863547-G-C
• chr7-124863547-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_015450.3(POT1):​c.349C>T​(p.Arg117Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,660 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. R117H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: POT1 NM_015450.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1 O:1
• Conservation: PhyloP100: 5.86
• Publications: 16 publications found

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

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911
• PP5: Variant 7-124863547-G-A is Pathogenic according to our data. Variant chr7-124863547-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 475082.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POT1	NM_015450.3	c.349C>T	p.Arg117Cys	missense_variant	Exon 8 of 19	ENST00000357628.8	NP_056265.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POT1	ENST00000357628.8	c.349C>T	p.Arg117Cys	missense_variant	Exon 8 of 19	2	NM_015450.3	ENSP00000350249.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251098 AF XY: 0.00000737

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461660 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727132

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111832

Other (OTH) AF: 0.00 AC: 0 AN: 60382

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tumor predisposition syndrome 3 Pathogenic:4 Other:1

Jun 05, 2025

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 117 of the POT1 protein (p.Arg117Cys). This variant is present in population databases (rs780936436, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of POT1 tumor predisposition syndrome (PMID: 26403419; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 475082). 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: 26403419). For these reasons, this variant has been classified as Pathogenic. -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Reported in 3 families with Li-Fraumeni-like and familial cardiac angiosarcoma -

-

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 (2/1461660 alleles, frequency : 0.00014%). Arginine at position 117 is an amino acid that appears to be highly conserved in evolution. The variant is located in the Telomeric single stranded DNA binding domain. The variant has been describred in 3 “Li-Fraumeni-like” families with multiple cancers including cardiosarcomas but also melanomas or lung cancers. In silico, in vitro and in vivo studies in cells showed that the variant reduces POT1 binding to telomeres and increases telomere length and fragility (PMID:26403419_2015). Another study by the same author showed the presence of a POT1 mutation in 20% of families with angiosarcomas and 10% of individuals with sporadic angio or cardiosarcoma (PMID:28853721_2017). The patient's phenotype and family history are compatible with the pathology associated with POT1 gene. -

Jun 17, 2025

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The POT1 c.1555G>A (p.Val519Ile) change has a maximum subpopulation frequency of 0.00088% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function. Functional studies demonstrated loss of telomere protection, with immunofluorescence and ChIP assays showing reduced telomere-bound POT1, and electrophoretic mobility shift assays confirming defective telomeric DNA binding. Co-immunoprecipitation revealed impaired TPP1 interaction, disrupting telomere recruitment. Carriers exhibited abnormally long telomeres, increased telomere fragility, and higher ?H2AX-positive cells, indicating telomere-associated DNA damage. HeLa cells expressing the variant showed telomere elongation, increased telomere-induced foci (TIFs), and multitelomeric signals, consistent with a dominant-negative effect. A mouse model expressing POT1 p.R117C showed telomerase-dependent telomere elongation, increased telomere fragility, and a mild increase in TIFs. Heterozygous mice developed cardiac angiosarcomas at higher rates, further confirming the role of this mutation in genomic instability and tumorigenesis (PMID: 26403419, 28853721, 1010260) . This variant has been reported in 3 TP53-negative Li-Fraumeni-like families with cardiac angiosarcoma and 1 family with breast angiosarcoma, with segregation observed in 1 family (PMID: 26403419). In summary, this variant meets criteria to be classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jun 09, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R117C variant (also known as c.349C>T), located in coding exon 4 of the POT1 gene, results from a C to T substitution at nucleotide position 349. The arginine at codon 117 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was reported in individual(s) with features consistent with POT1-related tumor predisposition syndrome (Calvete O et al. Nat Commun, 2015 Sep;6:8383; Baptista Freitas M et al. Eur J Hum Genet, 2024 Aug;32:980-986; Ambry internal data). This alteration segregated in three Li-Fraumeni like families, including members affected with cardiac angiosarcomas, and other soft tissue sarcomas. Individuals in these families were shown to have reduced telomere bound POT1 levels, abnormally long telomeres, and increased telomere fragility (Calvete O et al. Nat Commun, 2015 Sep;6:8383). Mouse modeling using both embryonic fibroblasts and tissues with the R117C alteration showed longer telomeres than wild-type controls and complementation assays showed that R117C exerts dominant-negative effects at telomeres (Martínez P et al. PLoS Genet, 2022 06;18:e1010260). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided Uncertain:1

Dec 17, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in Spanish families with angiosarcoma and other cancers (Calvete 2015); Published functional studies demonstrate reduced recruitment of POT1 protein to telomeres and increased DNA damage markers, but no impact on telomerase activity in patient cells (Calvete 2015, Calvete 2019); Not observed at a significant frequency in large population cohorts (Lek 2016); 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: 26403419, 28853721, 32033110, 28389767, 31510873) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.9
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.73		Loss of solvent accessibility (P = 0.0404);
MVP		0.67
MPC		2.3
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.40
gMVP		0.91
Mutation Taster		=22/78	disease causing

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

Other links and lift over

dbSNP: rs780936436; hg19: chr7-124503601; COSMIC: COSV105268145; COSMIC: COSV105268145;