rs587777627

chr19-50406444-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_002691.4(POLD1):c.1421T>C(p.Leu474Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. L474I) 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: 3.04

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 19-50406444-T-C is Pathogenic according to our data. Variant chr19-50406444-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 144003.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.1421T>C	p.Leu474Pro	missense_variant	12/27	ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7	c.1421T>C	p.Leu474Pro	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

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 10, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 08, 2021	- -
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: 24501277, 26133394, 28306219]. This variant is expected to disrupt protein structure [Myriad internal data]. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 21, 2022	For these reasons, this variant has been classified as Pathogenic. 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: 144003). This missense change has been observed in individual(s) with colorectal cancer, endometrial cancer, breast cancer and gastrointestinal stromal tumor (PMID: 24501277, 26133394, 28306219). 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 leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 474 of the POLD1 protein (p.Leu474Pro). -
risk factor, no assertion criteria provided	literature only	OMIM	Jul 01, 2014	- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2021

The p.L474P pathogenic mutation (also known as c.1421T>C), located in coding exon 11 of the POLD1 gene, results from a T to C substitution at nucleotide position 1421. The leucine at codon 474 is replaced by proline, an amino acid with similar properties. This variant is located within the highly conserved exonuclease domain of the POLD1 gene. This alteration was first reported in a female patient diagnosed with a colon cancer and a synchronous gastrointestinal stromal tumor (GIST) in the large bowel at age 36, whose family also met Amsterdam II criteria. Authors described this alteration as pathogenic, supported by cosegregation in the family, in silico predictions, previously published yeast assays, as well as the fact that this alteration's location is paralogous to the well described residue in POLE where the recurrent p.L424V mutation occurs (Valle L et al. Hum. Mol. Genet. 2014 Jul; 23(13):3506-12). The yeast based functional assay that the authors of Valle et al. describe was performed on the homologous residue (p.L479 Pol3) in yeast, and was shown to cause a mutator phenotype (Murphy K et al. Genome 2006 Apr; 49(4):403-10). This alteration has also been described in a woman with colorectal cancer and gastric polyps at age 23 as well as benign esophageal tumor at age 25. This alteration was also shown to segregate with disease in the family (Bellido F et al, Genet. Med. 2015 Jul;2). In addition, this alteration was identified in two Spanish families with colorectal cancer and breast cancer and is suggested to be a Spanish founder mutation. The tumor of one proband, which exhibited MSI and loss of MLH1 and PMS2 on IHC, had two MLH1 mutations. The authors posited that these somatic MLH1 mutations were a consequence of POLD1 inactivation (Ferrer-Avargues R et al. J Gene Med. 2017 Apr;19(4)). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.69	D;.;.;D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Pathogenic	3.7	H;.;.;H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.7	D;.;.;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.96
MutPred		0.95		Loss of stability (P = 0.0066);Loss of stability (P = 0.0066);Loss of stability (P = 0.0066);Loss of stability (P = 0.0066);
MVP		0.96
MPC		2.0
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.99
gMVP		0.99

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: rs587777627; hg19: chr19-50909701;