rs144143245

chr19-50409564-G-Cchr19-50409564-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_002691.4(POLD1):c.2052G>C(p.Gln684His) variant causes a missense change. The variant allele was found at a frequency of 0.000678 in 1,613,510 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q684Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (1 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12 B:9
• Conservation: PhyloP100: 4.16

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10002822).
• BP6: Variant 19-50409564-G-C is Benign according to our data. Variant chr19-50409564-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 239269.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=8, Benign=1}. Variant chr19-50409564-G-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 65 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLD1	NM_002691.4	c.2052G>C	p.Gln684His	missense_variant	17/27	ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7	c.2052G>C	p.Gln684His	missense_variant	17/27	1	NM_002691.4	P1

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152270 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000705

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000440 AC: 110 AN: 249976 Hom.: 0 AF XY: 0.000428 AC XY: 58 AN XY: 135428

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000832

Gnomad NFE exome AF: 0.000657

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000704 AC: 1029 AN: 1461122 Hom.: 1 Cov.: 32 AF XY: 0.000658 AC XY: 478 AN XY: 726898

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000626

Gnomad4 NFE exome AF: 0.000824

Gnomad4 OTH exome AF: 0.000629

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152388 Hom.: 0 Cov.: 32 AF XY: 0.000510 AC XY: 38 AN XY: 74524

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.000705

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000603 Hom.: 0

Bravo AF: 0.000457

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000453 AC: 55

EpiCase AF: 0.000436

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:6

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 03, 2022	The p.Gln684His variant in POLD1 has not been previously reported in individuals with colorectal cancer but has been identified in 49/65572 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs144143245). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Gln684His variant is uncertain. -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The POLD1 p.Gln684His variant was identified in 1 of 2092 proband chromosomes (frequency: 0.0005) from individuals or families with colon cancer (Raskin 2017). The variant was also identified in dbSNP (ID: rs144143245) as "With other allele", ClinVar (classified as likely benign by Invitae, GeneDx; as uncertain significance by Ambry Genetics and six clinical laboratories), MutDB, and in LOVD 3.0 (1x). The variant was not identified in Cosmic database. The variant was identified in control databases in 120 of 276056 chromosomes at a frequency of 0.0004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 23958 chromosomes (freq: 0.00008), Other in 1 of 6448 chromosomes (freq: 0.0002), Latino in 11 of 34410 chromosomes (freq: 0.0003), European in 79 of 125698 chromosomes (freq: 0.0006), Ashkenazi Jewish in 4 of 10132 chromosomes (freq: 0.0004), Finnish in 23 of 25792 chromosomes (freq: 0.0009); it was not observed in the East Asian and South Asian populations. The p.Gln684 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 2021	This variant is associated with the following publications: (PMID: 28608266, 29212164, 26648538, 29987844, 31285513, 31449058, 32041611) -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 19, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	POLD1: BS2 -

Colorectal cancer, susceptibility to, 10 Uncertain:5 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Molecular Oncology Laboratory, Hospital Clínico San Carlos	Jun 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 13, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jan 27, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Apr 06, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Sep 22, 2023	The POLD1 c.2052G>C (p.Gln684His) missense change has a maximum subpopulation frequency of 0.088% 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. This variant has been reported in individuals with colon cancer and/or colon polyposis (PMID: 29987844, 31285513, 29212164). 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. -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Apr 27, 2018	- -
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, criteria provided, single submitter	curation	Sema4, Sema4	Apr 08, 2021	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 10, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

POLD1-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 16, 2024

The POLD1 c.2052G>C variant is predicted to result in the amino acid substitution p.Gln684His. This variant has been reported in an individual with microsatellite stable colorectal cancer (Raskin et al. 2017. PubMed ID: 29212164), an individual with clinically suspected Lynch syndrome and loss of MSH2 in tumor tissue (the individual harbored additional variants; Kayser et al. 2018. PubMed ID: 29987844, Table S6, Patient 25), an individual with breast cancer (the individual harbored additional variants; Dominguez-Valentin et al. 2018. PubMed ID: 28608266, Table 2), an individual with attenuated adenomatous polyposis (Lorca et al. 2019. PubMed ID: 31285513, Table 2), and an individual with multiple primary cancer, who also carried several variants in other genes (Sylvester. 2021. PubMed ID: 34687117, patient MO111041 in Table S4 and Table S5). This variant is reported in 0.088% of alleles in individuals of European (Finnish) descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/239269/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.35
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.25	T;.;.;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.10	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;.;.;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.3	N;.;.;.
REVEL	Benign	0.19
Sift	Uncertain	0.028	D;.;.;.
Sift4G	Uncertain	0.033	D;D;D;D
Polyphen		0.73	P;.;.;P
Vest4		0.33
MutPred		0.47		Loss of stability (P = 0.0526);.;.;Loss of stability (P = 0.0526);
MVP		0.55
MPC		1.5
ClinPred		0.35	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.22
gMVP		0.51

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

Other links and lift over

dbSNP: rs144143245; hg19: chr19-50912821;