12-132661167-GAAAAA-GAAA

Variant names:

• chr12-132661167-GAA-G
• rs369732588
• NM_006231.4:c.2865-5_2865-4delTT

Variant summary

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

The NM_006231.4(POLE):​c.2865-5_2865-4delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00462 in 1,332,700 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000052 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0051 (0 hom.)
• Consequence: POLE NM_006231.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:6
• Conservation: PhyloP100: 0.200
• 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 -8 ACMG points.

• BP6: Variant 12-132661167-GAA-G is Benign according to our data. Variant chr12-132661167-GAA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 548827.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.2865-5_2865-4delTT		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.2865-5_2865-4delTT		splice_region intron	N/A	ENSP00000322570.5
	POLE	ENST00000535270.5	TSL:1	c.2784-5_2784-4delTT		splice_region intron	N/A	ENSP00000445753.1
	POLE	ENST00000537064.5	TSL:1	n.*1912-5_*1912-4delTT		splice_region intron	N/A	ENSP00000442578.1

Frequencies

GnomAD3 genomes AF: 0.0000521 AC: 7 AN: 134244 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000369

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000323

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0163 AC: 1742 AN: 106982 AF XY: 0.0154

Gnomad AFR exome AF: 0.00988

Gnomad AMR exome AF: 0.0236

Gnomad ASJ exome AF: 0.0260

Gnomad EAS exome AF: 0.0110

Gnomad FIN exome AF: 0.0185

Gnomad NFE exome AF: 0.0139

Gnomad OTH exome AF: 0.0205

GnomAD4 exome AF: 0.00513 AC: 6144 AN: 1198432 Hom.: 0 AF XY: 0.00549 AC XY: 3262 AN XY: 594378

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

African (AFR) AF: 0.00397 AC: 104 AN: 26202

American (AMR) AF: 0.0162 AC: 485 AN: 30014

Ashkenazi Jewish (ASJ) AF: 0.00901 AC: 184 AN: 20414

East Asian (EAS) AF: 0.00423 AC: 148 AN: 34974

South Asian (SAS) AF: 0.0115 AC: 761 AN: 66356

European-Finnish (FIN) AF: 0.00915 AC: 363 AN: 39670

Middle Eastern (MID) AF: 0.00404 AC: 18 AN: 4456

European-Non Finnish (NFE) AF: 0.00413 AC: 3826 AN: 926574

Other (OTH) AF: 0.00512 AC: 255 AN: 49772

⚠️ 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: 0.0000521 AC: 7 AN: 134268 Hom.: 0 Cov.: 31 AF XY: 0.0000464 AC XY: 3 AN XY: 64622

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

African (AFR) AF: 0.00 AC: 0 AN: 36184

American (AMR) AF: 0.000369 AC: 5 AN: 13552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3228

East Asian (EAS) AF: 0.00 AC: 0 AN: 4634

South Asian (SAS) AF: 0.00 AC: 0 AN: 4156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7746

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 268

European-Non Finnish (NFE) AF: 0.0000323 AC: 2 AN: 61876

Other (OTH) AF: 0.00 AC: 0 AN: 1782

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000157175), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 5

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	1	-	Carcinoma of colon (1)
-	-	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	Hereditary cancer-predisposing syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.20
Mutation Taster		=93/7	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: COSV57689572; COSMIC: COSV57689572;