12-132661167-GAAAAA-GAAAAAA

Variant names:

• chr12-132661167-G-GA
• rs369732588
• NM_006231.4:c.2865-4dupT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_006231.4(POLE):​c.2865-4dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (1 hom., cov: 31)
  • Exomes 𝑓: 0.13 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POLE NM_006231.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.191
• Publications: 4 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), Genomics England PanelApp, Ambry Genetics
• facial dysmorphism-immunodeficiency-livedo-short stature syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: Benign. The variant received -8 ACMG points.

• BP6: Variant 12-132661167-G-GA is Benign according to our data. Variant chr12-132661167-G-GA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 439266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2865-4dupT		splice_region intron	N/A	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.2865-4_2865-3insT		splice_region intron	N/A	ENSP00000322570.5	Q07864
	POLE	ENST00000535270.5	TSL:1	c.2784-4_2784-3insT		splice_region intron	N/A	ENSP00000445753.1	F5H1D6
	POLE	ENST00000537064.5	TSL:1	n.*1912-4_*1912-3insT		splice_region intron	N/A	ENSP00000442578.1	F5H7E4

Frequencies

GnomAD3 genomes AF: 0.00380 AC: 510 AN: 134160 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00798

Gnomad AMI AF: 0.00119

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00868

Gnomad EAS AF: 0.00151

Gnomad SAS AF: 0.00144

Gnomad FIN AF: 0.00634

Gnomad MID AF: 0.00680

Gnomad NFE AF: 0.00146

Gnomad OTH AF: 0.00452

GnomAD2 exomes AF: 0.0865 AC: 9249 AN: 106982 AF XY: 0.0846

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.0820

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.119

Gnomad FIN exome AF: 0.0787

Gnomad NFE exome AF: 0.0728

Gnomad OTH exome AF: 0.105

GnomAD4 exome AF: 0.130 AC: 140309 AN: 1080616 Hom.: 0 Cov.: 0 AF XY: 0.128 AC XY: 68817 AN XY: 537602

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.144 AC: 3374 AN: 23502

American (AMR) AF: 0.0749 AC: 2189 AN: 29220

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 2223 AN: 18862

East Asian (EAS) AF: 0.109 AC: 3398 AN: 31306

South Asian (SAS) AF: 0.135 AC: 8570 AN: 63448

European-Finnish (FIN) AF: 0.0876 AC: 3297 AN: 37644

Middle Eastern (MID) AF: 0.0917 AC: 384 AN: 4188

European-Non Finnish (NFE) AF: 0.134 AC: 111192 AN: 827290

Other (OTH) AF: 0.126 AC: 5682 AN: 45156

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00383 AC: 514 AN: 134184 Hom.: 1 Cov.: 31 AF XY: 0.00370 AC XY: 239 AN XY: 64574

African (AFR) AF: 0.00804 AC: 291 AN: 36176

American (AMR) AF: 0.00236 AC: 32 AN: 13552

Ashkenazi Jewish (ASJ) AF: 0.00868 AC: 28 AN: 3226

East Asian (EAS) AF: 0.00151 AC: 7 AN: 4630

South Asian (SAS) AF: 0.00144 AC: 6 AN: 4156

European-Finnish (FIN) AF: 0.00634 AC: 49 AN: 7724

Middle Eastern (MID) AF: 0.00746 AC: 2 AN: 268

European-Non Finnish (NFE) AF: 0.00146 AC: 90 AN: 61826

Other (OTH) AF: 0.00448 AC: 8 AN: 1784

Alfa AF: 0.00 Hom.: 5

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	POLE-related polyposis and colorectal cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.19
Mutation Taster		=96/4	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: rs369732588; hg19: chr12-133237753; COSMIC: COSV109428087;