rs140379348

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_002691.4(POLD1):c.1517G>A(p.Arg506His) variant causes a missense change. The variant allele was found at a frequency of 0.0000191 in 1,415,524 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R506C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000021 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 6.05

Publications

16 publications found

Variant links:

COSMIC-nc: COSV70954032

Genes affected

POLD1 (HGNC:9175): (DNA polymerase delta 1, catalytic subunit) This gene encodes the 125-kDa catalytic subunit of DNA polymerase delta. DNA polymerase delta possesses both polymerase and 3' to 5' exonuclease activity and plays a critical role in DNA replication and repair. Alternatively spliced transcript variants have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 6. [provided by RefSeq, Mar 2012]

POLD1 Gene-Disease associations (from GenCC):

POLD1-related polyposis and colorectal cancer syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
colorectal cancer, susceptibility to, 10
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
mandibular hypoplasia-deafness-progeroid syndrome
Inheritance: AD, AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Ambry Genetics, Orphanet, G2P
Polymerase proofreading-related adenomatous polyposis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
immunodeficiency 120
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
non-severe combined immunodeficiency due to polymerase delta deficiency
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

POLD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4 link	c.1517G>A	p.Arg506His	missense_variant	Exon 13 of 27	ENST00000440232.7	NP_002682.2	P28340A0A024R4F4Q59FA0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7 link	c.1517G>A	p.Arg506His	missense_variant	Exon 13 of 27	1	NM_002691.4	ENSP00000406046.1		P28340

Frequencies

GnomAD3 genomes

AF:

0.0000208

AC:

AN:

144186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000512

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000151

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000815

AC:

AN:

245380

AF XY:

0.00000752

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000550

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000907

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000189

AC:

AN:

1271338

Hom.:

Cov.:

AF XY:

0.0000159

AC XY:

AN XY:

630384

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28930

American (AMR)

AF:

0.00

AC:

AN:

38548

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18658

East Asian (EAS)

AF:

0.0000857

AC:

AN:

23334

South Asian (SAS)

AF:

0.0000239

AC:

AN:

83724

European-Finnish (FIN)

AF:

0.0000273

AC:

AN:

36602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4580

European-Non Finnish (NFE)

AF:

0.0000182

AC:

AN:

989272

Other (OTH)

AF:

0.0000210

AC:

AN:

47690

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000208

AC:

AN:

144186

Hom.:

Cov.:

AF XY:

0.0000143

AC XY:

AN XY:

70080

show subpopulations

African (AFR)

AF:

0.0000512

AC:

AN:

39074

American (AMR)

AF:

0.00

AC:

AN:

14384

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3430

East Asian (EAS)

AF:

0.00

AC:

AN:

4362

South Asian (SAS)

AF:

0.00

AC:

AN:

4082

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

304

European-Non Finnish (NFE)

AF:

0.0000151

AC:

AN:

66338

Other (OTH)

AF:

0.00

AC:

AN:

2012

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000681

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

May 20, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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; Observed in an individual with low grade glioma in published literature (PMID: 26580448); Published functional studies support no damaging effect: no effect on cell growth, sensitivity to DNA-damaging agents, protein abundance, or POLD1 mismatch repair activity, but slightly reduced DNA replication fidelity (PMID: 19966286, 34530183); This variant is associated with the following publications: (PMID: 21157497, 10074927, 27320729, 28368425, 7704014, 28687338, 33144657, 35620275, 34530183, 19966286, 26580448, 20951805) -

Aug 21, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The POLD1 c.1517G>A (p.Arg506His) variant has not been reported in the published literature in individuals with POLD1-related conditions. Functional studies have reported that this variant may reduce DNA replication fidelity (PMIDs: 19966286 (2010), 34530183 (2021)) and does not increase sensitivity of colorectal cancer cells to inhibitors (PMID 33144657 (2020)). The frequency of this variant in the general population, 0.000011 (3/276556 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Colorectal cancer, susceptibility to, 10

Uncertain:2

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 506 of the POLD1 protein (p.Arg506His). This variant is present in population databases (rs140379348, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 239242). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt POLD1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects POLD1 function (PMID: 19966286). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Oct 08, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Aug 13, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Jan 16, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R506H variant (also known as c.1517G>A), located in coding exon 12 of the POLD1 gene, results from a G to A substitution at nucleotide position 1517. The arginine at codon 506 is replaced by histidine, an amino acid with highly similar properties. In one yeast-based assay, this variant showed slightly reduced fidelity of DNA replication, which was compensated for by functional mismatch repair in wild type cells (Daee DL et al. Proc. Natl. Acad. Sci. U.S.A., 2010 Jan;107:157-62). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

not specified

Uncertain:1

Dec 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg506His variant in POLD1 has not been previously reported in individuals with colorectal cancer, but has been identified in 1/64598 of European chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs140379348). In vitro functional studies provide some evidence that the p. Arg506His variant may impact protein function (Daee 2010). However, these types of assays may not accurately represent biological function. Computational predic tion tools and conservation analysis do not provide strong support for or agains t an impact to the protein. In summary, the clinical significance of the p.Arg50 6His variant is uncertain. -

POLD1-related disorder

Uncertain:1

Dec 18, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The POLD1 c.1517G>A variant is predicted to result in the amino acid substitution p.Arg506His. This variant was previously identified in human colorectal adenocarcinoma cell lines defective in MMR, and showed reduced DNA proofreading activity, but also occurred with other causative variants (da Costa et al. 1995. PubMed ID: 7704014; Table 1, Yoshida et al. 2011. PubMed ID: 21157497; Prindle and Loeb. 2012. PubMed ID: 23065663; Nicolas et al. 2016. PubMed ID: 27320729). This variant is reported in 0.0051% of alleles in individuals of East Asian descent in gnomAD and is reported in ClinVar as a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/239242/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Colorectal cancer, susceptibility to, 10;C3715192:Mandibular hypoplasia-deafness-progeroid syndrome;C5935622:Immunodeficiency 120

Uncertain:1

Mar 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.31

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

D;.;.;D

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;.;D;D

M_CAP

Benign

0.047

MetaRNN

Uncertain

0.50

D;D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.9

M;.;.;M

PhyloP100

6.1

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-4.9

D;.;.;.

REVEL

Benign

0.18

Sift

Benign

0.062

T;.;.;.

Sift4G

Benign

0.080

T;T;T;T

Polyphen

0.76

P;.;.;P

Vest4

0.66

MVP

0.53

MPC

1.8

ClinPred

0.97

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.65

gMVP

0.74

Mutation Taster

=34/66

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over