NM_002691.4:c.1421T>C

Variant names:

• chr19-50406444-T-C
• rs587777627
• NM_002691.4:c.1421T>C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 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. 13/22 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
• Publications: 24 publications found

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 Gene-Disease associations (from GenCC):

• POLD1-related polyposis and colorectal cancer syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• colorectal cancer, susceptibility to, 10

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• mandibular hypoplasia-deafness-progeroid syndrome

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Ambry Genetics, Orphanet, G2P
• Polymerase proofreading-related adenomatous polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• immunodeficiency 120

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• non-severe combined immunodeficiency due to polymerase delta deficiency

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 33 uncertain in NM_002691.4
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 144003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4	c.1421T>C	p.Leu474Pro	missense_variant	Exon 12 of 27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.1421T>C	p.Leu474Pro	missense_variant	Exon 12 of 27	1	NM_002691.4	ENSP00000406046.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000429 Hom.: 0

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

Jun 10, 2016

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jul 01, 2014

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 08, 2021

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 144003). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POLD1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Apr 19, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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]. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jun 07, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
LIST_S2	Pathogenic	0.99	.;.;D;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
PhyloP100		3.0
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
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587777627; hg19: chr19-50909701;