19-50409206-C-T

Variant names:

• chr19-50409206-C-T
• rs45605236
• NM_002691.4:c.1977C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_002691.4(POLD1):​c.1977C>T​(p.Ile659Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00358 in 1,612,682 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (20 hom.)
• Consequence: POLD1 NM_002691.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 2.16
• Publications: 4 publications found

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

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.21).
• BP6: Variant 19-50409206-C-T is Benign according to our data. Variant chr19-50409206-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 221165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.16 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLD1	NM_002691.4	MANE Select	c.1977C>T	p.Ile659Ile	synonymous	Exon 16 of 27	NP_002682.2
	POLD1	NM_001308632.1		c.2055C>T	p.Ile685Ile	synonymous	Exon 15 of 26	NP_001295561.1
	POLD1	NM_001256849.1		c.1977C>T	p.Ile659Ile	synonymous	Exon 16 of 27	NP_001243778.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLD1	ENST00000440232.7	TSL:1 MANE Select	c.1977C>T	p.Ile659Ile	synonymous	Exon 16 of 27	ENSP00000406046.1
	POLD1	ENST00000595904.6	TSL:1	c.2055C>T	p.Ile685Ile	synonymous	Exon 16 of 27	ENSP00000472445.1
	POLD1	ENST00000599857.7	TSL:1	c.1977C>T	p.Ile659Ile	synonymous	Exon 16 of 27	ENSP00000473052.1

Frequencies

GnomAD3 genomes AF: 0.00283 AC: 431 AN: 152240 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00706

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000470

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00395

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00251 AC: 629 AN: 250800 AF XY: 0.00251

Gnomad AFR exome AF: 0.000865

Gnomad AMR exome AF: 0.00356

Gnomad ASJ exome AF: 0.00249

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000556

Gnomad NFE exome AF: 0.00386

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00365 AC: 5337 AN: 1460324 Hom.: 20 Cov.: 31 AF XY: 0.00355 AC XY: 2579 AN XY: 726580

African (AFR) AF: 0.000628 AC: 21 AN: 33462

American (AMR) AF: 0.00400 AC: 179 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00176 AC: 46 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86216

European-Finnish (FIN) AF: 0.000583 AC: 31 AN: 53206

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.00436 AC: 4839 AN: 1110792

Other (OTH) AF: 0.00348 AC: 210 AN: 60356

GnomAD4 genome AF: 0.00283 AC: 431 AN: 152358 Hom.: 3 Cov.: 32 AF XY: 0.00287 AC XY: 214 AN XY: 74518

African (AFR) AF: 0.000842 AC: 35 AN: 41584

American (AMR) AF: 0.00705 AC: 108 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000470 AC: 5 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00395 AC: 269 AN: 68034

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00361 Hom.: 1

Bravo AF: 0.00307

EpiCase AF: 0.00387

EpiControl AF: 0.00433

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Dec 30, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 25, 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.

Dec 21, 2016

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 25, 2021

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 03, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:4

Aug 26, 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 POLD1 c.1977C>T (p.Ile659Ile) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 288/119080 control chromosomes (1 homozygote) at a frequency of 0.0024185, which is approximately 170 times the estimated maximal expected allele frequency of a pathogenic POLD1 variant (0.0000142), suggesting this variant is likely a benign polymorphism. In addition, one clinical diagnostic laboratory in ClinVar has classified this variant as benign. The variant of interest has not been reported in affected individuals via publications, to our knowledge. Taken together, this variant is classified as Benign.

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

POLD1: BP4, BS2

Oct 11, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Hereditary cancer-predisposing syndrome Benign:4

Dec 01, 2017

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 06, 2025

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The synonymous variant NM_001308632.1(POLD1):c.2055C>T (p.Ile685=) has been reported to ClinVar as Benign/Likely benign with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 221165 as of 2025-01-02). The p.Ile685= variant is observed in 10/5,008 (0.1997%) alleles from individuals of 1kG All background in 1kG, which is greater than expected for the disorder. The p.Ile685= variant is not predicted to disrupt an existing splice site. For these reasons, this variant has been classified as Benign.

Feb 24, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

May 21, 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 Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Polymerase proofreading-related adenomatous polyposis Benign:1

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.Ile659= variant was not identified in the literature nor was it identified in the Cosmic or MutDB databases. The variant was identified in dbSNP (ID: rs45605236) “With other allele”, ClinVar (classified benign by Invitae, GeneDx, Ambry Genetics and Quest Diagnostics Nichols Institute San Juan Capistrano, and likely benign by Genetic Services Laboratory (University of Chicago)), Clinvitae (3x), and in control databases in 683 (1 homozygous) of 276786 chromosomes at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 25 of 23988 chromosomes (freq: 0.001), Other in 13 of 6462 chromosomes (freq: 0.002), Latino in 127 (1 homozygous) of 34414 chromosomes (freq: 0.004), European Non-Finnish in 481 of 126400 chromosomes (freq: 0.004), Ashkenazi Jewish in 24 of 10134 chromosomes (freq: 0.002), European Finnish in 12 of 25748 chromosomes (freq: 0.0005), and South Asian in 1 of 30776 chromosomes (freq: 0.00003) while not observed in the East Asian population. The p.Ile659= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.21
CADD	Benign	9.9
DANN	Benign	0.84
PhyloP100		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs45605236; hg19: chr19-50912463; COSMIC: COSV101486739; COSMIC: COSV101486739;