NM_002691.4:c.3305delC

Variant names:

• chr19-50417923-AC-A
• rs761614971
• NM_002691.4:c.3305delC

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PVS1_Moderate BS2

The NM_002691.4(POLD1):​c.3305delC​(p.Pro1102LeufsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000028 in 1,608,740 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: POLD1 NM_002691.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8 O:1
• Conservation: PhyloP100: 1.09

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]

ENSG00000142539 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00572 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BS2: High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4	c.3305delC	p.Pro1102LeufsTer22	frameshift_variant	Exon 27 of 27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.3305delC	p.Pro1102LeufsTer22	frameshift_variant	Exon 27 of 27	1	NM_002691.4	ENSP00000406046.1
ENSG00000142539	ENST00000599632.1	c.425+659delC		intron_variant	Intron 5 of 9	5		ENSP00000473233.1

Frequencies

GnomAD3 genomes AF: 0.0000464 AC: 7 AN: 150942 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000208 AC: 5 AN: 240886 Hom.: 0 AF XY: 0.00000763 AC XY: 1 AN XY: 131074

Gnomad AFR exome AF: 0.000201

Gnomad AMR exome AF: 0.0000295

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: 0.00000923

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000261 AC: 38 AN: 1457798 Hom.: 0 Cov.: 31 AF XY: 0.0000207 AC XY: 15 AN XY: 724982

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000464 AC: 7 AN: 150942 Hom.: 0 Cov.: 31 AF XY: 0.0000272 AC XY: 2 AN XY: 73616

Gnomad4 AFR AF: 0.000147

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000453

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Dec 02, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: POLD1 c.3305delC (p.Pro1102LeufsX22) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, however current evidence is not sufficient to establish loss of function as a mechanism for disease. c.3305delC (p.Pro1102LeufsX22) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 2.1e-05 in 240886 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3305delC in individuals affected with Mandibular Hypoplasia, Deafness, Progeroid Features, And Lipodystrophy Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 408095). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Sep 12, 2019

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:2

Feb 15, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 08, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in abnormal protein length as the last 6 amino acids are replaced with 21 different amino acids in a gene for which loss-of-function is not an established mechanism of disease; Observed in patients with pediatric leukemia, osteosarcoma, breast, or lung cancers (Lu et al., 2015; Alsultan et al., 2020; Mur et al., 2020; Zhang et al., 2015; Mirabello et al., 2020); This variant is associated with the following publications: (PMID: 32359129, 26689913, 32191290, 32792570, 26580448, 36451132) -

Colorectal cancer, susceptibility to, 10 Uncertain:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change results in a frameshift in the POLD1 gene (p.Pro1102Leufs*22). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 6 amino acid(s) of the POLD1 protein and extend the protein by 15 additional amino acid residues. This variant is present in population databases (rs761614971, gnomAD 0.01%). This frameshift has been observed in individual(s) with acute lymphoblastic leukemia, breast cancer, and/or osteosarcoma (PMID: 32191290, 32359129, 32792570). ClinVar contains an entry for this variant (Variation ID: 408095). 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. -

Jul 21, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

POLD1-related disorder Uncertain:1

Aug 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The POLD1 c.3305delC variant is predicted to result in a frameshift and premature protein termination (p.Pro1102Leufs*22). This variant results in the last 6 amino acids being disrupted and extends the protein by 15 additional amino acids (p.Pro1102Leufs*22). This variant has been reported in individuals with lung squamous cell carcinoma, acute leukemia, and breast cancer (Supplementary data 2, Lu et al. 2015. PubMed ID: 26689913; Alsultan et al. 2020. PubMed ID: 32359129; Mur et al. 2020. PubMed ID: 32792570). This variant is reported in 0.013% of alleles in individuals of African descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/408095/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary cancer-predisposing syndrome Uncertain:1

Sep 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3305delC variant, located in coding exon 26 of the POLD1 gene, results from a deletion of one nucleotide at nucleotide position 3305, causing a translational frameshift with a predicted alternate stop codon (p.P1102Lfs*22). This alteration occurs at the 3' terminus of thePOLD1 gene, is not expected to trigger nonsense-mediated mRNAdecay and results in the elongation of the protein by 15 amino acids. This frameshift impacts the last 6amino acids of the native protein. The exact functional effect of the altered amino acids is unknown. Based on the available evidence, the clinical significance of this variant remains unclear. -

Neoplasm Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.26		Position offset: 20

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

Publications

LitVar

Other links and lift over

dbSNP: rs761614971; hg19: chr19-50921180;