rs199545019

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_002691.4(POLD1):c.883G>A(p.Val295Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000462 in 1,591,384 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V295L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00045 ( 1 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:13O:1

Conservation

PhyloP100: 0.624

Publications

15 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03110981).

BP6

Variant 19-50402654-G-A is Benign according to our data. Variant chr19-50402654-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 239373.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4 link	c.883G>A	p.Val295Met	missense_variant	Exon 8 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.883G>A	p.Val295Met	missense_variant	Exon 8 of 27	1	NM_002691.4	ENSP00000406046.1		P28340

Frequencies

GnomAD3 genomes

AF:

0.000591

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.000553

AC:

121

AN:

218624

AF XY:

0.000549

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00125

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000558

Gnomad OTH exome

AF:

0.00127

GnomAD4 exome

AF:

0.000449

AC:

646

AN:

1439016

Hom.:

Cov.:

AF XY:

0.000422

AC XY:

301

AN XY:

713450

show subpopulations

African (AFR)

AF:

0.000211

AC:

AN:

33198

American (AMR)

AF:

0.00160

AC:

AN:

41152

Ashkenazi Jewish (ASJ)

AF:

0.00105

AC:

AN:

25606

East Asian (EAS)

AF:

0.0000257

AC:

AN:

38922

South Asian (SAS)

AF:

0.000345

AC:

AN:

84064

European-Finnish (FIN)

AF:

0.0000194

AC:

AN:

51528

Middle Eastern (MID)

AF:

0.00461

AC:

AN:

4986

European-Non Finnish (NFE)

AF:

0.000389

AC:

428

AN:

1100194

Other (OTH)

AF:

0.00108

AC:

AN:

59366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

119

159

199

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000591

AC:

AN:

152368

Hom.:

Cov.:

AF XY:

0.000537

AC XY:

AN XY:

74514

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41592

American (AMR)

AF:

0.00189

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000588

AC:

AN:

68030

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000635

Hom.:

Bravo

AF:

0.000714

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.000372

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:13Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:6Other:1

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

POLD1: BP4, BS1, BS2 -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 15, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Uncertain:2Benign:2

Mar 15, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is denoted POLD1 c.883G>A at the cDNA level, p.Val295Met (V295M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). Bellido et al. (2015) identified this variant in two kindreds characterized by familial or early-onset mismatch repair proficient colorectal cancer and/or APC and MUTYH-negative polyposes. In one family POLD1 Val295Met was present in both a woman with early-onset colorectal cancer and her mother, who was diagnosed with colorectal cancer at age 70. In the second family, POLD1 Val296Met was observed in trans with a second POLD1 missense variant, Asp316Gly, which the authors interpreted as pathogenic. While the mother in this kindred, who was affected with breast and endometrial cancer, harbored both variants, a daughter affected with both colorectal and endometrial cancer only inherited POLD1 Asp316Gly. POLD1 Val295Met was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Valine and Methionine share similar properties, this is considered a conservative amino acid substitution. POLD1 Val295Met occurs at a position that is conserved in mammals and is not located in a known functional domain (Tahirov 2009, Preston 2010). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether POLD1 Val295Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Mar 07, 2021

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: POLD1 c.883G>A (p.Val295Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00055 in 218624 control chromosomes. The observed variant frequency is approximately 40 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLD1 causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is benign. c.883G>A has been reported in the literature as a VUS in at-least two families with a history of cancers but no conclusive co-segregation with disease (example, Bellido_2016, Buchanan_2018) These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments some citing overlapping evidence utilized in the context of this evaluation (likely benign, n=2; benign, n=1; VUS, n=3). Based on the evidence outlined above, the variant was classified as likely benign. -

Sep 01, 2021

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNA sequence analysis of the POLD1 gene demonstrated a sequence change, c.883G>A, in exon 8 that results in an amino acid change, p.Val295Met. This sequence change does not appear to have been previously described in patients with POLD1-related disorders and has been described in the gnomAD database with a population frequency of 0.14% in Ashkenazi Jewish subpopulation (dbSNP rs199545019). The p.Val295Met change affects a poorly conserved amino acid residue located in a domain of the POLD1 protein that is known to be functional. The p.Val295Met substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these evidences and the lack of functional studies, the clinical significance of the p.Val295Met change remains unknown at this time. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Colorectal cancer, susceptibility to, 10

Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:2

Jan 27, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Jun 25, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

Carcinoma of colon

Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The POLD1 p.Val295Met variant was identified in 2 of 1058 proband chromosomes (frequency: 0.002) from individuals or families with early-onset nonpolyposis CRC (Bellido 2016). The variant was also identified in dbSNP (ID: rs199545019) as "With Uncertain significance allele", and in ClinVar (classified as likely benign by Invitae; as uncertain significance by GeneDx and two clinical laboratories). The variant was identified in control databases in 120 of 243858 chromosomes at a frequency of 0.0005 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: Other in 9 of 5878 chromosomes (freq: 0.002), Latino in 35 of 30486 chromosomes (freq: 0.001), European in 52 of 109472 chromosomes (freq: 0.0005), Ashkenazi Jewish in 14 of 9360 chromosomes (freq: 0.002), and South Asian in 10 of 28292 chromosomes (freq: 0.0004); it was not observed in the African, East Asian, or Finnish populations. The p.Val295 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 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. This variant is classified as a variant of uncertain significance. -

POLD1-related disorder

Benign:1

Jun 20, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

T;.;.;T

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.97

.;.;D;D

M_CAP

Benign

0.017

MetaRNN

Benign

0.031

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.090

N;.;.;N

PhyloP100

0.62

PrimateAI

Uncertain

0.50

PROVEAN

Benign

0.41

N;.;.;.

REVEL

Benign

0.057

Sift

Benign

0.092

T;.;.;.

Sift4G

Benign

0.081

T;T;T;T

Polyphen

0.41

B;.;.;B

Vest4

0.40

MVP

0.53

MPC

0.21

ClinPred

0.014

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.071

gMVP

0.45

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

Details are displayed if max score is > 0.2

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