NM_015450.3(POT1):c.349C>T (p.Arg117Cys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 2, 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:: RCV002456249.3

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:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002612921	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Nov 2, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26403419, 35727838 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002612921

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Nov 2, 2023)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

A mutation in the POT1 gene is responsible for cardiac angiosarcoma in TP53-negative Li-Fraumeni-like families.

Calvete O, Martinez P, Garcia-Pavia P, Benitez-Buelga C, Paumard-Hernández B, Fernandez V, Dominguez F, Salas C, Romero-Laorden N, Garcia-Donas J, Carrillo J, Perona R, Triviño JC, Andrés R, Cano JM, Rivera B, Alonso-Pulpon L, Setien F, Esteller M, Rodriguez-Perales S, Bougeard G, Frebourg T, et al.

Nat Commun. 2015 Sep 25;6:8383. doi: 10.1038/ncomms9383.

PubMed [citation]

PMID:: 26403419
PMCID:: PMC4598567

A mouse model for Li-Fraumeni-Like Syndrome with cardiac angiosarcomas associated to POT1 mutations.

Martínez P, Sánchez-Vázquez R, Ferrara-Romeo I, Serrano R, Flores JM, Blasco MA.

PLoS Genet. 2022 Jun;18(6):e1010260. doi: 10.1371/journal.pgen.1010260.

PubMed [citation]

PMID:: 35727838
PMCID:: PMC9212151

Details of each submission

From Ambry Genetics, SCV002612921.2

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

Description

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 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.

#	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

Last Updated: Sep 29, 2024

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