chr19-50399376-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_002691.4(POLD1):​c.208G>T​(p.Val70Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000887 in 1,612,884 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00094 ( 1 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:7O:1

Conservation

PhyloP100: -0.0980
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.014080226).
BP6
Variant 19-50399376-G-T is Benign according to our data. Variant chr19-50399376-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225288.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=8, Benign=2, Likely_benign=4, not_provided=1}. Variant chr19-50399376-G-T is described in Lovd as [Likely_benign].
BS2
High AC in GnomAd4 at 57 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POLD1NM_002691.4 linkc.208G>T p.Val70Phe missense_variant Exon 3 of 27 ENST00000440232.7 NP_002682.2 P28340A0A024R4F4Q59FA0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POLD1ENST00000440232.7 linkc.208G>T p.Val70Phe missense_variant Exon 3 of 27 1 NM_002691.4 ENSP00000406046.1 P28340

Frequencies

GnomAD3 genomes
AF:
0.000375
AC:
57
AN:
152194
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.000750
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000303
AC:
76
AN:
251112
Hom.:
0
AF XY:
0.000332
AC XY:
45
AN XY:
135742
show subpopulations
Gnomad AFR exome
AF:
0.000247
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000590
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000940
AC:
1373
AN:
1460572
Hom.:
1
Cov.:
31
AF XY:
0.000914
AC XY:
664
AN XY:
726652
show subpopulations
Gnomad4 AFR exome
AF:
0.000179
Gnomad4 AMR exome
AF:
0.0000894
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.00119
Gnomad4 OTH exome
AF:
0.000646
GnomAD4 genome
AF:
0.000374
AC:
57
AN:
152312
Hom.:
0
Cov.:
32
AF XY:
0.000242
AC XY:
18
AN XY:
74490
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000750
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000704
Hom.:
0
Bravo
AF:
0.000400
TwinsUK
AF:
0.00108
AC:
4
ALSPAC
AF:
0.00234
AC:
9
ExAC
AF:
0.000264
AC:
32
EpiCase
AF:
0.000763
EpiControl
AF:
0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:9Benign:7Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:2Other:1
Jan 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

POLD1: BP4, BS1 -

Apr 03, 2020
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The POLD1 c.208G>T; p.Val70Phe variant (rs147911699) is reported in the literature in an individual with colon cancer (Ghazani 2017). This variant is also reported in ClinVar (Variation ID: 225288). It is found in the general population with an overall allele frequency of 0.03% (89/282506 alleles) in the Genome Aggregation Database. The valine at codon 70 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Ghazani AA et al. Assigning clinical meaning to somatic and germ-line whole-exome sequencing data in a prospective cancer precision medicine study. Genet Med. 2017 Jul;19(7):787-795. -

Jan 26, 2021
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colorectal cancer (Ghazani 2017); This variant is associated with the following publications: (PMID: 28125075) -

-
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. -

Aug 13, 2024
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BP4 -

Colorectal cancer, susceptibility to, 10 Uncertain:3Benign:1
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 17, 2023
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The POLD1 c.208G>T (p.Val70Phe) missense change has a maximum subpopulation frequency of 0.062% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with POLD1-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Aug 11, 2016
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 28, 2019
Mendelics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Uncertain:1Benign:2
Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 21, 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.208G>T, in exon 3 that results in an amino acid change, p.Val70Phe. This sequence change has been described in the gnomAD database with a frequency of 0.062% in the European sub-population (dbSNP rs147911699). The p.Val70Phe change has been identified in an individual with colon cancer (PMID: 28125075). The p.Val70Phe change affects a poorly conserved amino acid residue located in a domain of the POLD1 protein that is not known to be functional. The p.Val70Phe substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Val70Phe change remains unknown at this time. -

Apr 06, 2020
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Feb 28, 2024
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. -

Apr 09, 2018
True Health Diagnostics
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Carcinoma of colon Uncertain:1
Jan 01, 2016
CSER _CC_NCGL, University of Washington
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: research

- -

Colorectal cancer, susceptibility to, 10;C3715192:Mandibular hypoplasia-deafness-progeroid syndrome Uncertain:1
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

POLD1-related disorder Benign:1
May 04, 2023
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
0.055
BayesDel_addAF
Benign
-0.67
T
BayesDel_noAF
Benign
-0.74
CADD
Benign
0.060
DANN
Benign
0.90
DEOGEN2
Benign
0.20
T;.;.;.;T;.
Eigen
Benign
-1.7
Eigen_PC
Benign
-1.7
FATHMM_MKL
Benign
0.0013
N
LIST_S2
Benign
0.38
.;.;T;T;T;T
M_CAP
Benign
0.0061
T
MetaRNN
Benign
0.014
T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.55
N;.;.;.;N;.
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-0.40
N;.;.;.;.;.
REVEL
Benign
0.029
Sift
Benign
0.062
T;.;.;.;.;.
Sift4G
Benign
0.068
T;T;T;T;T;T
Polyphen
0.0
B;.;.;.;B;.
Vest4
0.16
MVP
0.24
MPC
0.25
ClinPred
0.0081
T
GERP RS
-4.8
Varity_R
0.026
gMVP
0.35

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs147911699; hg19: chr19-50902633; COSMIC: COSV70955356; COSMIC: COSV70955356; API