NM_002691.4:c.56G>T

Variant names:

• chr19-50398907-G-T
• rs3218773
• NM_002691.4:c.56G>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_002691.4(POLD1):​c.56G>T​(p.Arg19Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,448,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. R19C) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.22
• Publications: 15 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21891564).
• BP6: Variant 19-50398907-G-T is Benign according to our data. Variant chr19-50398907-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 841540.

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.56G>T	p.Arg19Leu	missense	Exon 2 of 27	NP_002682.2
	POLD1	NM_001308632.1		c.56G>T	p.Arg19Leu	missense	Exon 1 of 26	NP_001295561.1
	POLD1	NM_001256849.1		c.56G>T	p.Arg19Leu	missense	Exon 2 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.56G>T	p.Arg19Leu	missense	Exon 2 of 27	ENSP00000406046.1
	POLD1	ENST00000595904.6	TSL:1	c.56G>T	p.Arg19Leu	missense	Exon 2 of 27	ENSP00000472445.1
	POLD1	ENST00000599857.7	TSL:1	c.56G>T	p.Arg19Leu	missense	Exon 2 of 27	ENSP00000473052.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1448142 Hom.: 0 Cov.: 33 AF XY: 0.00000139 AC XY: 1 AN XY: 719014

African (AFR) AF: 0.0000300 AC: 1 AN: 33320

American (AMR) AF: 0.00 AC: 0 AN: 42658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25692

East Asian (EAS) AF: 0.00 AC: 0 AN: 39304

South Asian (SAS) AF: 0.00 AC: 0 AN: 83954

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4168

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106966

Other (OTH) AF: 0.00 AC: 0 AN: 59748

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Colorectal cancer, susceptibility to, 10 Uncertain:1

Dec 06, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not available"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with POLD1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with leucine at codon 19 of the POLD1 protein (p.Arg19Leu). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and leucine.

Hereditary cancer-predisposing syndrome Benign:1

Aug 18, 2025

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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		3.2
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.065
Sift	Uncertain	0.024	D
Sift4G	Benign	0.19	T
Polyphen		0.020	B
Vest4		0.49
MutPred		0.18		Loss of methylation at R17 (P = 0.0481)
MVP		0.47
MPC		0.23
ClinPred		0.93	D
GERP RS		3.1
PromoterAI		-0.019	Neutral
Varity_R		0.16
gMVP		0.39
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs3218773; hg19: chr19-50902164;