19-50406452-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PP3_Moderate

The NM_002691.4(POLD1):c.1429G>A(p.Val477Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000113 in 1,599,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. V477L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 6.17

Publications

8 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: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 31 uncertain in NM_002691.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.901

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002691.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
POLD1	NM_002691.4	MANE Select	c.1429G>A	p.Val477Met	missense	Exon 12 of 27	NP_002682.2
POLD1	NM_001308632.1		c.1429G>A	p.Val477Met	missense	Exon 11 of 26	NP_001295561.1
POLD1	NM_001256849.1		c.1429G>A	p.Val477Met	missense	Exon 12 of 27	NP_001243778.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
POLD1	ENST00000440232.7	TSL:1 MANE Select	c.1429G>A	p.Val477Met	missense	Exon 12 of 27	ENSP00000406046.1
POLD1	ENST00000595904.6	TSL:1	c.1429G>A	p.Val477Met	missense	Exon 12 of 27	ENSP00000472445.1
POLD1	ENST00000599857.7	TSL:1	c.1429G>A	p.Val477Met	missense	Exon 12 of 27	ENSP00000473052.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000133

AC:

AN:

224972

AF XY:

0.0000165

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000200

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000117

AC:

AN:

1447586

Hom.:

Cov.:

AF XY:

0.0000125

AC XY:

AN XY:

718870

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33152

American (AMR)

AF:

0.00

AC:

AN:

42494

Ashkenazi Jewish (ASJ)

AF:

0.0000388

AC:

AN:

25790

East Asian (EAS)

AF:

0.00

AC:

AN:

39004

South Asian (SAS)

AF:

0.0000355

AC:

AN:

84550

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52166

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.0000109

AC:

AN:

1104924

Other (OTH)

AF:

0.0000167

AC:

AN:

59786

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

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:

0.00000657

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41416

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000341

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Colorectal cancer, susceptibility to, 10

Uncertain:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 477 of the POLD1 protein (p.Val477Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 537029). 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 expected to disrupt POLD1 protein function with a positive predictive value of 80%. 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.

Mar 30, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary cancer-predisposing syndrome

Uncertain:2

May 07, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM1_Supporting, BS3_Supporting c.1429G>A, located in exon 12 of the POLD1 gene, is predicted to result in the substitution of valine by methionine at codon 477, p.(Val477Met). This variant affects a (potentially) clinically important functional domain (PM1_Supporting). This variant is found in 3/244552 alleles at a frequency of 0,001% in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing, and the REVEL meta-predictor score (0.664) for this variant is indeterminate regarding the effect that it may have on protein function. Assays in yeast reported that this variant shows polymerase proofreading function similar to WT (PMID:�38219146, 29717118) (BS3_Supporting). To our knowledge, no relevant clinical data have been reported for this variant. This variant has been reported in the ClinVar database (4x uncertain significance) and in LOVD (1x uncertain significance). Based on currently available information, the variant c.1429G>A should be considered an uncertain significance variant according to ACMG/AMP classification guidelines.

Oct 05, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.V477M variant (also known as c.1429G>A), located in coding exon 11 of the POLD1 gene, results from a G to A substitution at nucleotide position 1429. The valine at codon 477 is replaced by methionine, an amino acid with highly similar properties. This alteration has been detected in an endometrial tumor that displayed a mutation spectrum typical of microsatellite instability; suggesting that p.V477M does not impact exonuclease function (Haradhvala NJ et al. Nat Commun, 2018 May;9:1746). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Polymerase proofreading-related adenomatous polyposis;C3896578:Familial colorectal cancer type X

Uncertain:1

Mar 10, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Uncertain:1

Feb 10, 2023

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; Has not been previously published as a pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 29056344, 29717118, 26648449, 32686686, 11988770, 20951805)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.50

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.90

MetaSVM

Benign

-0.51

MutationAssessor

Pathogenic

3.7

PhyloP100

6.2

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.56

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.65

MutPred

0.87

Gain of MoRF binding (P = 0.1631)

MVP

0.72

MPC

1.6

ClinPred

0.99

GERP RS

4.9

Varity_R

0.88

gMVP

0.87

Mutation Taster

=18/82

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over