NM_015450.3(POT1):c.349C>T (p.Arg117Cys) AND Tumor predisposition syndrome 3

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Dec 8, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000543907.10

Allele description [Variation Report for NM_015450.3(POT1):c.349C>T (p.Arg117Cys)]

NM_015450.3(POT1):c.349C>T (p.Arg117Cys)

Gene:

POT1:protection of telomeres 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q31.33

Genomic location:

Preferred name:

NM_015450.3(POT1):c.349C>T (p.Arg117Cys)

HGVS:

NC_000007.14:g.124863547G>A
NG_029232.1:g.71437C>T
NM_001042594.2:c.-45C>T
NM_015450.3:c.349C>TMANE SELECT
NP_056265.2:p.Arg117Cys
NC_000007.13:g.124503601G>A
NM_015450.2:c.349C>T
NR_003102.2:n.792C>T
NR_003103.2:n.792C>T
NR_003104.2:n.792C>T

Protein change:

R117C

Links:

dbSNP: rs780936436

NCBI 1000 Genomes Browser:

rs780936436

Molecular consequence:

NM_001042594.2:c.-45C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_015450.3:c.349C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_003102.2:n.792C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_003103.2:n.792C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_003104.2:n.792C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Tumor predisposition syndrome 3 (TPDS3)
Synonyms:: Melanoma, cutaneous malignant, susceptibility to, 10; LONG TELOMERE SYNDROME, POT1-RELATED; Glioma susceptibility 9
Identifiers:: MONDO: MONDO:0014368; MedGen: C4014476; Orphanet: 618; OMIM: 615848

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000655186	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 8, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26403419, 28492532
SCV001478027	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 26403419, 33119245
SCV004805901	Center of Human Genetics, Hôpital Erasme	no assertion criteria provided	Likely pathogenic	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26403419, 28853721

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000655186

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 8, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV001478027

GeneReviews

no classification provided

not provided

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

SCV004805901

Center of Human Genetics, Hôpital Erasme

no assertion criteria provided

Likely pathogenic

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

POT1 Tumor Predisposition..

Henry ML, Osborne J, Else T.

2020 Oct 29 [updated 2022 Mar 10]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

PubMed [citation]

PMID:: 33119245

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000655186.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 475082). 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: 26403419). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneReviews, SCV001478027.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center of Human Genetics, Hôpital Erasme, SCV004805901.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Sarcoma at 65, cutaneous melanoma at 66, colon cancer at 67 + family history of cancers

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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