rs41554817

chr19-50402732-G-Achr19-50402732-G-Cchr19-50402732-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

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). Synonymous variant affecting the same amino acid position (i.e. G321G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00046 (1 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:17 B:2
• Conservation: PhyloP100: 7.17

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 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: {Uncertain_significance=12, Likely_benign=2}.
• BS2: High AC in GnomAd at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLD1	NM_002691.4	c.961G>A	p.Gly321Ser	missense_variant	8/27	ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7	c.961G>A	p.Gly321Ser	missense_variant	8/27	1	NM_002691.4	P1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152240 Hom.: 0 Cov.: 33

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: 90 AN: 241452 Hom.: 0 AF XY: 0.000396 AC XY: 52 AN XY: 131464

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.: 1 Cov.: 34 AF XY: 0.000494 AC XY: 352 AN XY: 711980

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: 40 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21 AN XY: 74378

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.: 0

Bravo AF: 0.000283

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000437 AC: 53

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:17 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:7

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 2023	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 13, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 12, 2022	The frequency of this variant in the general population, 0.00066 (82/124328 chromosomes in European (Non-Finnish) subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with colorectal polyps and colorectal cancer (PMIDs: 26648449 (2015), 25938944 (2015), 30827058 (2018), and 33193653 (2020)). 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Colorectal cancer, susceptibility to, 10 Uncertain:3 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Aug 05, 2021	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/variant/19-50905989-G-A). In silico tools are not in agreement about the effect of this variant on protein function, but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in the literature in individuals with a personal and/or family history of colorectal cancer (PS4_supporting; PMID: 26648449, 30827058, 33193653), in an individual with colon polyps (PMID: 25938944), in an individual with multiple endocrine neoplasia, type II (PMID: 30680046), and in non-cancer controls (PMID: 30267214). One individual with >100 colorectal polyps and colorectal cancer diagnosed at age 37 also carried a heterozygous pathogenic variant in MUTYH (PMID: 30827058). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PS4_supporting. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 27, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 19, 2023	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. -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 03, 2021	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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Sep 09, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Sep 29, 2017	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Feb 06, 2024

- -

POLD1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 21, 2023

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). Two additional unrelated patients with multiple colorectal polyps and colorectal cancer were also reported to have this variant; 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). 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). This variant is reported in 0.066% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted as both a variant of uncertain significance and likely benign in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/221136/). 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

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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 “with uncertain significance allele”, 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

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

Jul 02, 2018

- -

Colorectal cancer, susceptibility to, 10;C3715192:Mandibular hypoplasia-deafness-progeroid syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Uncertain	0.050
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;.;.;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.50	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M;.;.;M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.86	D
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	T
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

Other links and lift over

dbSNP: rs41554817; hg19: chr19-50905989;