rs397514632

Variant names:

• chr19-50406456-G-A
• rs397514632
• NM_002691.4:c.1433G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-50406456-G-A
• chr19-50406456-G-C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PM5 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. S478R) 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:6 O:1
• Conservation: PhyloP100: 5.21
• Publications: 77 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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-50406455-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 4082309.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 40044.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.1433G>A	p.Ser478Asn	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.1433G>A	p.Ser478Asn	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

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Aug 01, 2015

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 18, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: 23263490]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Feb 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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 and astrocytoma (PMID: 23263490, 25559809, 26344056). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 40044). 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%. Experimental studies have shown that this missense change affects POLD1 function (PMID: 23263490). For these reasons, this variant has been classified as Pathogenic. -

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. -

not provided Pathogenic:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Aug 06, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S478N variant (also known as c.1433G>A), located in coding exon 11 of the POLD1 gene, results from a G to A substitution at nucleotide position 1433. The serine at codon 478 is replaced by asparagine, an amino acid with highly similar properties. This variant was reported in multiple individuals with features consistent with POLD1-related polymerase proofreading-associated polyposis. In addition, this variant was reported to segregate with disease in multiple families (Palles C et al. Nat Genet, 2013 Feb;45:136-44; Chubb D et al. J Clin Oncol, 2015 Feb;33:426-32; Arora S et al. Gastroenterology, 2015 Dec;149:1872-1883.e9; Jansen AML et al. Fam Cancer, 2020 Jan;19:1-10; Ito T et al. Jpn J Clin Oncol, 2020 Sep;50:1080-1083). In multiple assays testing POLD1 function, this variant showed functionally abnormal results (Palles C et al. Nat Genet, 2013 Feb;45:136-44; Oh DY et al. Hum Mutat, 2020 May;41:913-920). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be 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
LIST_S2	Pathogenic	0.99	.;.;D;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
PhyloP100		5.2
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
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397514632; hg19: chr19-50909713; COSMIC: COSV70955559; COSMIC: COSV70955559;