rs41554817

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2

The NM_002691.4(POLD1):c.961G>A(p.Gly321Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000438 in 1,591,596 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00046 ( 1 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:18B:3

Conservation

PhyloP100: 7.17

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 Likely_benign. Variant got -5 ACMG points.

BP6

Variant 19-50402732-G-A is Benign according to our data. Variant chr19-50402732-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 221136.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=12}.

BS2

High AC in GnomAd4 at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4 link	c.961G>A	p.Gly321Ser	missense_variant	Exon 8 of 27	ENST00000440232.7	NP_002682.2	P28340A0A024R4F4Q59FA0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7 link	c.961G>A	p.Gly321Ser	missense_variant	Exon 8 of 27	1	NM_002691.4	ENSP00000406046.1		P28340

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

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:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000373

AC:

AN:

241452

Hom.:

AF XY:

0.000396

AC XY:

AN XY:

131464

show subpopulations

Gnomad AFR exome

AF:

0.0000645

Gnomad AMR exome

AF:

0.000207

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000337

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000725

Gnomad OTH exome

AF:

0.000342

GnomAD4 exome

AF:

0.000456

AC:

657

AN:

1439356

Hom.:

Cov.:

AF XY:

0.000494

AC XY:

352

AN XY:

711980

show subpopulations

Gnomad4 AFR exome

AF:

0.0000908

Gnomad4 AMR exome

AF:

0.000182

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000704

Gnomad4 FIN exome

AF:

0.000135

Gnomad4 NFE exome

AF:

0.000556

Gnomad4 OTH exome

AF:

0.000389

GnomAD4 genome

AF:

0.000263

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000508

Hom.:

Bravo

AF:

0.000283

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000437

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:18Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:8

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 02, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30827058, 30680046, 20951805, 25938944, 27320729, 26648449, 28188185, 29120461, 33193653, 33332384, 34326862, 35264596, 37088804) -

Jun 13, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 02, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 09, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The POLD1 c.961G>A (p.Gly321Ser) variant has been reported in the published literature in individuals with colorectal polyps and colorectal cancer (PMIDs: 33193653 (2020), 30827058 (2019), 26648449 (2015), 25938944 (2015)). Functional studies demonstrated that this variant was damaging to protein function (PMID: 26648449 (2015)). The frequency of this variant in the general population, 0.00097 (25/25792 chromosomes in Swedish subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Colorectal cancer, susceptibility to, 10

Uncertain:3Benign:1

Jul 05, 2024

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The POLD1 c.961G>A (p.Gly321Ser) missense change has a maximum subpopulation frequency of 0.066% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge, functional studies have not been performed. This variant has been reported in the literature in individuals with a personal and/or family history of colorectal cancer (PMID: 26648449, 30827058, 33193653). It was also reported in individuals with multiple endocrine neoplasia (PMID: 30680046), and hereditary breast/ovarian cancer (PMID: 38136308). This variant co-occurred with a pathogenic mutation in MUTYH in one individual diagnosed with colorectal cancer who presented with >100 colorectal polyps (PMID: 30827058). This variant has also been detected in non-cancer controls (PMID: 30267214). 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. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 19, 2023

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

Oct 27, 2016

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Sep 29, 2017

True Health Diagnostics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 09, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Nov 03, 2021

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. -

not specified

Uncertain:1Benign:1

Feb 03, 2025

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: POLD1 c.961G>A (p.Gly321Ser) results in a non-conservative amino acid change located in the DNA-directed DNA polymerase, family B, exonuclease domain (IPR006133) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 241452 control chromosomes, predominantly at a frequency of 0.00073 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1168 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLD1 causing Mandibular Hypoplasia, Deafness, Progeroid Features, And Lipodystrophy Syndrome phenotype (6.3e-07). c.961G>A has been reported in the literature in individuals affected with multiple polyps and colorectal cancer (CRC) without family segregation (Weren_2015, Elsayed_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Mandibular Hypoplasia, Deafness, Progeroid Features, And Lipodystrophy Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30827058, 25938944). ClinVar contains an entry for this variant (Variation ID: 221136). Based on the evidence outlined above, the variant was classified as likely benign. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

POLD1-related disorder

Uncertain:1

Jul 30, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The POLD1 c.961G>A variant is predicted to result in the amino acid substitution p.Gly321Ser. This variant has been reported in an individual with adenomatous polyps and a family history of colorectal cancer or adenomatous polyposis (Weren et al. 2015. PubMed ID: 25938944) and an individual suspected of having Lynch syndrome (Jansen et al. 2016. PubMed ID: 26648449). It was also reported as a variant of uncertain significance in a study of individuals with early-onset colorectal cancer or familial colorectal cancer (Djursby et al. 2020. PubMed ID: 33193653) and in a study of patients with a suspected hereditary tumor syndrome (Henn et al. 2019. PubMed ID: 30680046). Two additional unrelated patients with multiple colorectal polyps and colorectal cancer were also reported to have this variant; however, the variant did not co-segregate with disease in one family and co-segregation analysis was unavailable for the other family (Table 2 and Figure 1A, Elsayed et al. 2019. PubMed ID: 30827058). This variant is reported in 0.066% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted as a variant of uncertain significance and likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/221136/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Carcinoma of colon

Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The POLD1 p.Gly321Ser variant was identified in 5 of 1364 proband chromosomes (frequency: 0.004) from individuals with colorectal and medullary thyroid cancer (Weren 2015, Jansen 2016, Elsayed 2019, Henn 2019). The variant was identified in dbSNP (rs41554817) as â€šÃ„Ãºwith uncertain significance alleleâ€šÃ„Ã¹, ClinVar (interpreted as uncertain significance by Invitae, Ambry Genetics and 7 others). The variant was identified in control databases in 88 of 268,044 chromosomes at a frequency of 0.000328 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 3 of 23418 chromosomes (freq: 0.0001), Other in 1 of 6224 chromosomes (freq: 0.0002), Latino in 7 of 33,760 chromosomes (freq: 0.0002), European in 75 of 122,102 chromosomes (freq: 0.0006), Finnish in 1 of 24,360 chromosomes (freq: 0.00004), and South Asian in 1 of 29,884 chromosomes (freq: 0.00003). The variant was not observed in the Ashkenazi Jewish and East Asian populations. The variant affects the exonuclease domain of POLD1, but functional analysis would be needed to determine if there is a deleterious effect on the protein. The p.Gly321 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. This variant is classified as a variant of uncertain significance -

Familial colorectal cancer

Uncertain:1

Jul 02, 2018

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Benign

-0.055

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

T;.;.;T

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;.;D;D

M_CAP

Benign

0.051

MetaRNN

Uncertain

0.50

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.8

M;.;.;M

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-5.4

D;.;.;.

REVEL

Uncertain

0.36

Sift

Uncertain

0.0090

D;.;.;.

Sift4G

Benign

0.11

T;T;T;T

Polyphen

0.88

P;.;.;P

Vest4

0.77

MVP

0.56

MPC

0.75

ClinPred

0.35

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.85

gMVP

0.75

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