NM_002691.4:c.88C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_002691.4(POLD1):c.88C>T(p.Arg30Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,593,262 control chromosomes in the GnomAD database, including 132 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R30Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0071 ( 8 hom., cov: 32)

Exomes 𝑓: 0.011 ( 124 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20

Conservation

PhyloP100: 0.865

Publications

20 publications found

Variant links:

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: Benign. The variant received -12 ACMG points.

BP6

Variant 19-50398939-C-T is Benign according to our data. Variant chr19-50398939-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 221163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4 link	c.88C>T	p.Arg30Trp	missense_variant	Exon 2 of 27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7 link	c.88C>T	p.Arg30Trp	missense_variant	Exon 2 of 27	1	NM_002691.4	ENSP00000406046.1

Frequencies

GnomAD3 genomes

AF:

0.00713

AC:

1085

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00183

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00621

Gnomad ASJ

AF:

0.00922

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00931

Gnomad FIN

AF:

0.00207

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0117

Gnomad OTH

AF:

0.00669

GnomAD2 exomes

AF:

0.00821

AC:

1770

AN:

215634

AF XY:

0.00887

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.00649

Gnomad ASJ exome

AF:

0.00806

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00271

Gnomad NFE exome

AF:

0.0112

Gnomad OTH exome

AF:

0.0116

GnomAD4 exome

AF:

0.0108

AC:

15496

AN:

1440938

Hom.:

124

Cov.:

AF XY:

0.0108

AC XY:

7736

AN XY:

714662

show subpopulations

African (AFR)

AF:

0.00238

AC:

AN:

33234

American (AMR)

AF:

0.00694

AC:

286

AN:

41202

Ashkenazi Jewish (ASJ)

AF:

0.00794

AC:

203

AN:

25558

East Asian (EAS)

AF:

0.0000512

AC:

AN:

39076

South Asian (SAS)

AF:

0.0119

AC:

990

AN:

82962

European-Finnish (FIN)

AF:

0.00302

AC:

157

AN:

51996

Middle Eastern (MID)

AF:

0.0155

AC:

AN:

4324

European-Non Finnish (NFE)

AF:

0.0119

AC:

13106

AN:

1103040

Other (OTH)

AF:

0.0102

AC:

606

AN:

59546

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

858

1716

2573

3431

4289

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

496

992

1488

1984

2480

<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:

0.00712

AC:

1085

AN:

152324

Hom.:

Cov.:

AF XY:

0.00648

AC XY:

483

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00183

AC:

AN:

41566

American (AMR)

AF:

0.00621

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00922

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00932

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00207

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0117

AC:

796

AN:

68032

Other (OTH)

AF:

0.00662

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

114

171

228

285

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0103

Hom.:

Bravo

AF:

0.00713

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.0150

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.0140

AC:

120

ExAC

AF:

0.00707

AC:

856

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Dec 09, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 05, 2016

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 17, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:6

Sep 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

POLD1: BP4, BS1, BS2

Aug 25, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The c.88C>T (p.Arg30Trp) in POLD1 gene is a missense change that involves a non-conserved nucleotide and 4/5 in silico tools predict benign outcome. The variant is present in the control population dataset of ExAC at an overall frequency 0.013 (671/52972 chrs tested) including 5 homozygotes. This frequency exceeds the estimated maximum allele frequency for a pathogenic allele in this gene (0.0000142). The variant was identified in a clinical case, which also carried a known pathogenic mutation, c.68_69delAG, in BRCA1 gene. The variant is cited as Benign by a reputable database/clinical laboratory. Taking together, the variant was classified as Benign.

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The POLD1 p.Arg30Trp variant was identified in 1 of 58 proband chromosomes (frequency: 0.02) from individuals or families with HNPCC (Talseth-Palmer 2015). The variant was also identified in dbSNP (ID: rs3218772) as "With Benign allele", ClinVar (classified as benign by Invitae, Counsyl, GeneDx, Ambry Genetics and three other clinical laboratories), Cosmic (1x in prostate tissue), and MutDB. The variant was identified in control databases in 1935 of 241054 chromosomes (13 homozygous) at a frequency of 0.008, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 1228 of 108476 chromosomes (freq: 0.01), South Asian in 299 of 26820 chromosomes (freq: 0.01), African in 28 of 21060 chromosomes (freq: 0.001), Other in 62 of 5816 chromosomes (freq: 0.01), Latino in 183 of 30048 chromosomes (freq: 0.006), Ashkenazi Jewish in 74 of 9266 chromosomes (freq: 0.0079), and Finnish in 61 of 22694 chromosomes (freq: 0.0026), while the variant was not observed in the East Asian population. The p.Arg30 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Colorectal cancer, susceptibility to, 10

Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 10, 2016

Counsyl

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary cancer-predisposing syndrome

Benign:3

Jan 27, 2025

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense variant NM_001308632.1(POLD1):c.88C>T (p.Arg30Trp) has been reported to ClinVar as Benign/Likely benign with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 221163 as of 2025-01-02). . There is a moderate physicochemical difference between arginine and tryptophan. The gene POLD1 has a low rate of benign missense variation as indicated by a high For these reasons, this variant has been classified as Benign

Dec 01, 2017

True Health Diagnostics

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

May 20, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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

Benign:1

Mar 16, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

T;.;.;.;T;.

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.079

LIST_S2

Benign

0.0

.;.;T;T;T;T

MetaRNN

Benign

0.0071

T;T;T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.34

N;.;.;.;N;.

PhyloP100

0.86

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.38

N;.;.;.;.;.

REVEL

Benign

0.028

Sift

Benign

0.043

D;.;.;.;.;.

Sift4G

Uncertain

0.047

D;D;T;D;D;T

Vest4

0.29

ClinPred

0.0043

GERP RS

1.0

PromoterAI

-0.040

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.041

gMVP

0.25

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.23

Position offset: 18

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over