rs397514632

chr19-50406456-G-Achr19-50406456-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_002691.4(POLD1):c.1433G>A(p.Ser478Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S478G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 5.21

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 Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.891
• PP5: Variant 19-50406456-G-A is Pathogenic according to our data. Variant chr19-50406456-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLD1	NM_002691.4	c.1433G>A	p.Ser478Asn	missense_variant	12/27	ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7	c.1433G>A	p.Ser478Asn	missense_variant	12/27	1	NM_002691.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Colorectal cancer, susceptibility to, 10 Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 18, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 04, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects POLD1 function (PMID: 23263490). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 40044). This missense change has been observed in individual(s) with colorectal cancer, endometrial cancer and astrocytoma (PMID: 23263490, 25559809, 26344056). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 478 of the POLD1 protein (p.Ser478Asn). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 10, 2016	- -
risk factor, no assertion criteria provided	literature only	OMIM	Aug 01, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 19, 2023	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 23263490]. This variant is expected to disrupt protein structure [Myriad internal data]. -

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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The POLD1 p.Ser478Asn variant was identified in 2 of 1302 proband chromosomes (frequency: 0.002) from individuals or families with colorectal cancer (Arora 2015, Chubb 2015). The variant was also identified in dbSNP (ID: rs397514632) as “With other allele”, ClinVar (classified as pathogenic by Invitae, likely pathogenic by Counsyl, and as a risk factor by OMIM). The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Ser478 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. However, this variant is located in the exonuclease domain of the enzyme and is suggested to affect the secondary structure of this active site (Briggs 2013, Palles 2013). The variant has also been reported to segregate with disease in several affected individuals in at least two unrelated families (Briggs 2013, Palles 2013). A functional study in yeast demonstrated that this variant resulted in a 12-fold increase in mutation rate as compared to wild type (Palles 2013). 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, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;.;.;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Benign	-0.37	T
MutationAssessor	Pathogenic	4.2	H;.;.;H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.8	D;.;.;.
REVEL	Uncertain	0.38
Sift	Uncertain	0.0020	D;.;.;.
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.80
MutPred		0.69		Loss of disorder (P = 0.1939);Loss of disorder (P = 0.1939);Loss of disorder (P = 0.1939);Loss of disorder (P = 0.1939);
MVP		0.76
MPC		1.5
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.96
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs397514632; hg19: chr19-50909713; COSMIC: COSV70955559; COSMIC: COSV70955559;