NM_002691.4(POLD1):c.2284C>T (p.Arg762Ter) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 15, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000657763.2

Allele description [Variation Report for NM_002691.4(POLD1):c.2284C>T (p.Arg762Ter)]

NM_002691.4(POLD1):c.2284C>T (p.Arg762Ter)

Gene:

POLD1:DNA polymerase delta 1, catalytic subunit [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19q13.33

Genomic location:

Preferred name:

NM_002691.4(POLD1):c.2284C>T (p.Arg762Ter)

HGVS:

NC_000019.10:g.50413775C>T
NG_033800.1:g.34453C>T
NM_001256849.1:c.2284C>T
NM_001308632.1:c.2362C>T
NM_002691.4:c.2284C>TMANE SELECT
NP_001243778.1:p.Arg762Ter
NP_001295561.1:p.Arg788Ter
NP_002682.2:p.Arg762Ter
LRG_785t1:c.2284C>T
LRG_785t2:c.2362C>T
LRG_785:g.34453C>T
LRG_785p1:p.Arg762Ter
LRG_785p2:p.Arg788Ter
NC_000019.9:g.50917032C>T
NM_002691.2:c.2284C>T
NM_002691.3:c.2284C>T
NR_046402.2:n.2329C>T

Protein change:

R762*

Links:

dbSNP: rs769650989

NCBI 1000 Genomes Browser:

rs769650989

Molecular consequence:

NR_046402.2:n.2329C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_001256849.1:c.2284C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001308632.1:c.2362C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_002691.4:c.2284C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000779516	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Mar 29, 2018)	germline	clinical testing	Citation Link,
SCV004219064	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (May 15, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000779516

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Mar 29, 2018)

germline

clinical testing

Citation Link,

SCV004219064

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(May 15, 2023)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

Citations

PubMed

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

Details of each submission

From GeneDx, SCV000779516.1

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

Description

This variant is denoted POLD1 c.2284C>T at the cDNA level and p.Arg762Ter (R762X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in colon cancer (Giannakis 2014). While some missense variants in POLD1 have been recognized as an underlying cause of Polymerase Proofreading-Associated Polyposis (PPAP), there are no data at this time to support that loss-of-function variants confer the same cancer risks. We therefore consider this variant to be of uncertain significance with respect to cancer.

#	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, SCV004219064.1

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

Description

This variant is predicted to cause the premature termination of POLD1 protein synthesis, however loss of function of POLD1 has not been clearly established as a mechanism of disease. This variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000008 (2/248472 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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: Feb 20, 2024

ClinVar

Relating variation to medicine