chr19-50399376-G-T

Position:

chr19-50399376-G-T

Variant summary

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

The ENST00000440232.7(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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V70I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00094 ( 1 hom. )

Consequence

POLD1
ENST00000440232.7 missense

Scores

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]

POLD1 links:

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: {Benign=2, Likely_benign=4, Uncertain_significance=8, 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/exons	MANE	Protein	UniProt
POLD1	NM_002691.4 linkuse as main transcript	c.208G>T	p.Val70Phe	missense_variant	3/27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7 linkuse as main transcript	c.208G>T	p.Val70Phe	missense_variant	3/27	1	NM_002691.4	ENSP00000406046	P1

Frequencies

GnomAD3 genomes

AF:

0.000375

AC:

AN:

152194

Hom.:

Cov.:

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:

AN:

251112

Hom.:

AF XY:

0.000332

AC XY:

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.:

Cov.:

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:

AN:

152312

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

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.:

Bravo

AF:

0.000400

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00234

AC:

ExAC

AF:

0.000264

AC:

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

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2021	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 03, 2020	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 13, 2024	BP4 -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	POLD1: BP4, BS1 -

Colorectal cancer, susceptibility to, 10

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 11, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jan 17, 2023	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. -

not specified

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 21, 2021	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. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 06, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 28, 2024	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. -
Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Apr 09, 2018	- -

Carcinoma of colon

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Jan 01, 2016

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

POLD1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 04, 2023

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

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

LIST_S2

Benign

0.38

.;.;T;T;T;T

M_CAP

Benign

0.0061

MetaRNN

Benign

0.014

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.55

N;.;.;.;N;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.41

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over