NM_015450.3(POT1):c.233T>C (p.Ile78Thr) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Dec 8, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV001755899.13

Allele description [Variation Report for NM_015450.3(POT1):c.233T>C (p.Ile78Thr)]

NM_015450.3(POT1):c.233T>C (p.Ile78Thr)

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.233T>C (p.Ile78Thr)

HGVS:

NC_000007.14:g.124870933A>G
NG_029232.1:g.64051T>C
NM_001042594.2:c.-138-7293T>C
NM_015450.3:c.233T>CMANE SELECT
NP_056265.2:p.Ile78Thr
NC_000007.13:g.124510987A>G
NM_015450.2:c.233T>C
NR_003102.2:n.676T>C
NR_003103.2:n.676T>C
NR_003104.2:n.676T>C

Protein change:

I78T; ILE78THR

Links:

OMIM: 606478.0015; dbSNP: rs947005337

NCBI 1000 Genomes Browser:

rs947005337

Molecular consequence:

NM_001042594.2:c.-138-7293T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_015450.3:c.233T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_003102.2:n.676T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_003103.2:n.676T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_003104.2:n.676T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001986362	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Dec 8, 2023)	germline	clinical testing	Citation Link,
SCV004219100	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Feb 3, 2023)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 34193977, 30586141, 30451293, 24686846, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001986362

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Dec 8, 2023)

germline

clinical testing

Citation Link,

SCV004219100

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(Feb 3, 2023)

unknown

clinical testing

PubMed (5)
[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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Germline POT1 variants can predispose to myeloid and lymphoid neoplasms.

Lim TL, Lieberman DB, Davis AR, Loren AW, Hausler R, Bigdeli A, Li Y, Powers J, Raper A, Regeneron Genetics Center, Carty SA, Nathanson KL, Bagg A, Hexner EO, Maxwell KN, Morrissette JJD, Babushok DV.

Leukemia. 2022 Jan;36(1):283-287. doi: 10.1038/s41375-021-01335-w. Epub 2021 Jun 30. No abstract available.

PubMed [citation]

PMID:: 34193977
PMCID:: PMC8716670

Association of the POT1 Germline Missense Variant p.I78T With Familial Melanoma.

Wong K, Robles-Espinoza CD, Rodriguez D, Rudat SS, Puig S, Potrony M, Wong CC, Hewinson J, Aguilera P, Puig-Butille JA, Bressac-de Paillerets B, Zattara H, van der Weyden L, Fletcher CDM, Brenn T, Arends MJ, Quesada V, Newton-Bishop JA, Lopez-Otin C, Bishop DT, Harms PW, Johnson TM, et al.

JAMA Dermatol. 2019 May 1;155(5):604-609. doi: 10.1001/jamadermatol.2018.3662.

PubMed [citation]

PMID:: 30586141
PMCID:: PMC6506889

See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV001986362.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Observed in individuals with multiple primary melanomas and/or with familial melanoma; however, several unaffected carriers were also identified (PMID: 24686846, 30451293, 37140166, 36876055); Observed in individuals with lymphoid or myeloid malignancies, as well as individuals with thyroid cancer (PMID: 34193977, 37140166); Published functional studies demonstrate a damaging effect: disrupted telomere binding and telomere elongation (PMID: 37140166, 30586141); Not observed at significant frequency in large population cohorts (gnomAD); 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: 24686846, 30451293, 32015491, 31259407, Offin_2020_Abstract, 32155570, 34648949, 32172474, 32987645, 34193977, 36624550, 28393830, 36876055, 37140166, 30586141)

#	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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004219100.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The frequency of this variant in the general population, 0.0003 (3/9890 chromosomes in Ashkenazi Jewish 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 an individual with melanoma (PMID: 30586141 (2018), 30451293 (2018), 24686846 (2014)) and chronic lymphocytic leukemia (PMID: 34193977 (2021)). This variant has also been shown to have a deleterious effect on POT1 protein function (PMID: 30586141 (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.

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

Last Updated: Sep 29, 2024

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