12-132661167-GAAAAA-GAAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_006231.4(POLE):​c.2865-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0425 in 134,162 control chromosomes in the GnomAD database, including 209 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (209 hom., cov: 31)
  • Exomes 𝑓: 0.21 (106 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:10
• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), 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 -16 ACMG points.

• BP6: Variant 12-132661167-GA-G is Benign according to our data. Variant chr12-132661167-GA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 695292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.129 is higher than 0.05.

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.2865-4delT		splice_region intron	N/A	NP_006222.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLE	ENST00000320574.10	TSL:1 MANE Select	c.2865-4delT		splice_region intron	N/A	ENSP00000322570.5
	POLE	ENST00000535270.5	TSL:1	c.2784-4delT		splice_region intron	N/A	ENSP00000445753.1
	POLE	ENST00000537064.5	TSL:1	n.*1912-4delT		splice_region intron	N/A	ENSP00000442578.1

Frequencies

GnomAD3 genomes AF: 0.0425 AC: 5696 AN: 134136 Hom.: 202 Cov.: 31

Gnomad AFR AF: 0.0115

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.0344

Gnomad EAS AF: 0.00194

Gnomad SAS AF: 0.0228

Gnomad FIN AF: 0.0486

Gnomad MID AF: 0.0272

Gnomad NFE AF: 0.0450

Gnomad OTH AF: 0.0334

GnomAD2 exomes AF: 0.385 AC: 41182 AN: 106982 AF XY: 0.388

Gnomad AFR exome AF: 0.362

Gnomad AMR exome AF: 0.402

Gnomad ASJ exome AF: 0.354

Gnomad EAS exome AF: 0.358

Gnomad FIN exome AF: 0.357

Gnomad NFE exome AF: 0.399

Gnomad OTH exome AF: 0.366

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.213 AC: 212152 AN: 996606 Hom.: 106 Cov.: 0 AF XY: 0.215 AC XY: 106028 AN XY: 493402

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

African (AFR) AF: 0.187 AC: 3948 AN: 21162

American (AMR) AF: 0.334 AC: 8821 AN: 26384

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 3754 AN: 16754

East Asian (EAS) AF: 0.208 AC: 5233 AN: 25170

South Asian (SAS) AF: 0.225 AC: 13208 AN: 58756

European-Finnish (FIN) AF: 0.234 AC: 7456 AN: 31830

Middle Eastern (MID) AF: 0.192 AC: 713 AN: 3722

European-Non Finnish (NFE) AF: 0.207 AC: 160156 AN: 771860

Other (OTH) AF: 0.216 AC: 8863 AN: 40968

⚠️ 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 AF: 0.0425 AC: 5708 AN: 134162 Hom.: 209 Cov.: 31 AF XY: 0.0447 AC XY: 2886 AN XY: 64570

African (AFR) AF: 0.0115 AC: 416 AN: 36180

American (AMR) AF: 0.134 AC: 1816 AN: 13548

Ashkenazi Jewish (ASJ) AF: 0.0344 AC: 111 AN: 3228

East Asian (EAS) AF: 0.00194 AC: 9 AN: 4632

South Asian (SAS) AF: 0.0231 AC: 96 AN: 4154

European-Finnish (FIN) AF: 0.0486 AC: 376 AN: 7732

Middle Eastern (MID) AF: 0.0299 AC: 8 AN: 268

European-Non Finnish (NFE) AF: 0.0450 AC: 2781 AN: 61794

Other (OTH) AF: 0.0331 AC: 59 AN: 1784

Alfa AF: 0.00842 Hom.: 5

Bravo AF: 0.0420

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Colorectal cancer, susceptibility to, 12 (1)
-	-	1	Colorectal cancer, susceptibility to, 12;C3554576:Facial dysmorphism-immunodeficiency-livedo-short stature syndrome;C5193036:Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency (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		=91/9	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: COSV57673646; COSMIC: COSV57673646;