rs1060500865

Variant names:

• chr12-132676098-T-A
• rs1060500865
• NM_006231.4:c.1016A>T

Your query was ambiguous. Multiple possible variants found:

• chr12-132676098-T-A
• chr12-132676098-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_006231.4(POLE):​c.1016A>T​(p.Asp339Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000553 in 1,445,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. D339N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 7.98
• Publications: 1 publications found

Genes affected

POLE (HGNC:9177): (DNA polymerase epsilon, catalytic subunit) This gene encodes the catalytic subunit of DNA polymerase epsilon. The enzyme is involved in DNA repair and chromosomal DNA replication. Mutations in this gene have been associated with colorectal cancer 12 and facial dysmorphism, immunodeficiency, livedo, and short stature. [provided by RefSeq, Sep 2013]

POLE Gene-Disease associations (from GenCC):

• POLE-related polyposis and colorectal cancer syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• colorectal cancer, susceptibility to, 12

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• facial dysmorphism-immunodeficiency-livedo-short stature syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency

  Inheritance: AR Classification: STRONG Submitted by: G2P
• IMAGe syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Polymerase proofreading-related adenomatous polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006231.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLE	NM_006231.4	MANE Select	c.1016A>T	p.Asp339Val	missense	Exon 10 of 49	NP_006222.2	Q07864

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLE	ENST00000320574.10	TSL:1 MANE Select	c.1016A>T	p.Asp339Val	missense	Exon 10 of 49	ENSP00000322570.5	Q07864
	POLE	ENST00000535270.5	TSL:1	c.935A>T	p.Asp312Val	missense	Exon 9 of 48	ENSP00000445753.1	F5H1D6
	POLE	ENST00000537064.5	TSL:1	n.*63A>T		non_coding_transcript_exon	Exon 10 of 49	ENSP00000442578.1	F5H7E4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000407 AC: 1 AN: 245574 AF XY: 0.00000753

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000304

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000553 AC: 8 AN: 1445688 Hom.: 0 Cov.: 29 AF XY: 0.00000834 AC XY: 6 AN XY: 719856

African (AFR) AF: 0.00 AC: 0 AN: 32780

American (AMR) AF: 0.0000232 AC: 1 AN: 43066

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25898

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.00 AC: 0 AN: 85000

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53040

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00000636 AC: 7 AN: 1100788

Other (OTH) AF: 0.00 AC: 0 AN: 59764

GnomAD4 genome Cov.: 33

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000113

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (4)
-	3	-	Colorectal cancer, susceptibility to, 12 (3)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		8.0
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.93	P
Vest4		0.80
MutPred		0.59		Gain of catalytic residue at N336 (P = 0)
MVP		0.51
MPC		0.91
ClinPred		0.93	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.79
Mutation Taster		=25/75	disease causing

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: rs1060500865; hg19: chr12-133252684; COSMIC: COSV100265864;