NM_015450.3(POT1):c.1615C>T (p.Gln539Ter) AND Tumor predisposition syndrome 3

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 11, 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:: RCV001901143.4

Allele description [Variation Report for NM_015450.3(POT1):c.1615C>T (p.Gln539Ter)]

NM_015450.3(POT1):c.1615C>T (p.Gln539Ter)

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.1615C>T (p.Gln539Ter)

HGVS:

NC_000007.14:g.124827285G>A
NG_029232.1:g.107699C>T
NM_001042594.2:c.1222C>T
NM_015450.3:c.1615C>TMANE SELECT
NP_001036059.1:p.Gln408Ter
NP_056265.2:p.Gln539Ter
NC_000007.13:g.124467339G>A
NM_015450.2:c.1615C>T
NR_003102.2:n.2178C>T
NR_003103.2:n.1969C>T
NR_003104.2:n.2155C>T

Protein change:

Q408*

Links:

dbSNP: rs2116415082

NCBI 1000 Genomes Browser:

rs2116415082

Molecular consequence:

NR_003102.2:n.2178C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_003103.2:n.1969C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_003104.2:n.2155C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_001042594.2:c.1222C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_015450.3:c.1615C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV002160458	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 11, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32155570, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002160458

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 11, 2023)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The enigma of excessively long telomeres in cancer: lessons learned from rare human POT1 variants.

Gong Y, Stock AJ, Liu Y.

Curr Opin Genet Dev. 2020 Feb;60:48-55. doi: 10.1016/j.gde.2020.02.002. Epub 2020 Mar 8. Review.

PubMed [citation]

PMID:: 32155570
PMCID:: PMC7230001

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

Details of each submission

From Invitae, SCV002160458.3

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

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 1395307). This variant has not been reported in the literature in individuals affected with POT1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln539*) in the POT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POT1 are known to be pathogenic (PMID: 32155570).

#	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: Jun 17, 2024

ClinVar

Relating variation to medicine