19-50402729-G-T

Variant names:

• chr19-50402729-G-T
• rs1488821062
• NM_002691.4:c.958G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002691.4(POLD1):​c.958G>T​(p.Ala320Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A320T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.93
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002691.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLD1	NM_002691.4	MANE Select	c.958G>T	p.Ala320Ser	missense	Exon 8 of 27	NP_002682.2
	POLD1	NM_001308632.1		c.958G>T	p.Ala320Ser	missense	Exon 7 of 26	NP_001295561.1
	POLD1	NM_001256849.1		c.958G>T	p.Ala320Ser	missense	Exon 8 of 27	NP_001243778.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLD1	ENST00000440232.7	TSL:1 MANE Select	c.958G>T	p.Ala320Ser	missense	Exon 8 of 27	ENSP00000406046.1
	POLD1	ENST00000595904.6	TSL:1	c.958G>T	p.Ala320Ser	missense	Exon 8 of 27	ENSP00000472445.1
	POLD1	ENST00000599857.7	TSL:1	c.958G>T	p.Ala320Ser	missense	Exon 8 of 27	ENSP00000473052.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1440228 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 712584

African (AFR) AF: 0.00 AC: 0 AN: 33056

American (AMR) AF: 0.00 AC: 0 AN: 44006

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25734

East Asian (EAS) AF: 0.00 AC: 0 AN: 39142

South Asian (SAS) AF: 0.00 AC: 0 AN: 85374

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51910

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4216

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1097666

Other (OTH) AF: 0.00 AC: 0 AN: 59124

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Colorectal cancer, susceptibility to, 10 Uncertain:1

Nov 02, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 320 of the POLD1 protein (p.Ala320Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 823345). 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 not expected to disrupt POLD1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Hereditary cancer-predisposing syndrome Uncertain:1

Jul 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A320S variant (also known as c.958G>T), located in coding exon 7 of the POLD1 gene, results from a G to T substitution at nucleotide position 958. The alanine at codon 320 is replaced by serine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.9
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.24
Sift	Benign	0.052	T
Sift4G	Benign	0.074	T
Polyphen		0.90	P
Vest4		0.61
MutPred		0.53		Loss of catalytic residue at A320 (P = 0.0123)
MVP		0.47
MPC		0.70
ClinPred		0.95	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.61
Mutation Taster		=59/41	polymorphism

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: rs1488821062; hg19: chr19-50905986; COSMIC: COSV70956700; COSMIC: COSV70956700;