chr12-132661167-G-GAA

Variant names:

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

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_2865-4dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000903 in 1,368,040 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00098 (0 hom.)
• Consequence: POLE NM_006231.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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-GAA is Benign according to our data. Variant chr12-132661167-G-GAA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 801260.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_2865-4dupTT		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_2865-3insTT		splice_region intron	N/A	ENSP00000322570.5	Q07864
	POLE	ENST00000535270.5	TSL:1	c.2784-4_2784-3insTT		splice_region intron	N/A	ENSP00000445753.1	F5H1D6
	POLE	ENST00000537064.5	TSL:1	n.*1912-4_*1912-3insTT		splice_region intron	N/A	ENSP00000442578.1	F5H7E4

Frequencies

GnomAD3 genomes AF: 0.000156 AC: 21 AN: 134284 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000129

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000178

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00214 AC: 229 AN: 106982 AF XY: 0.00214

Gnomad AFR exome AF: 0.00334

Gnomad AMR exome AF: 0.00172

Gnomad ASJ exome AF: 0.00260

Gnomad EAS exome AF: 0.00321

Gnomad FIN exome AF: 0.00274

Gnomad NFE exome AF: 0.00175

Gnomad OTH exome AF: 0.00232

GnomAD4 exome AF: 0.000985 AC: 1215 AN: 1233756 Hom.: 0 Cov.: 0 AF XY: 0.00104 AC XY: 638 AN XY: 612260

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

African (AFR) AF: 0.00159 AC: 43 AN: 27002

American (AMR) AF: 0.00168 AC: 52 AN: 30898

Ashkenazi Jewish (ASJ) AF: 0.00180 AC: 38 AN: 21084

East Asian (EAS) AF: 0.00113 AC: 41 AN: 36162

South Asian (SAS) AF: 0.00270 AC: 185 AN: 68468

European-Finnish (FIN) AF: 0.00109 AC: 45 AN: 41154

Middle Eastern (MID) AF: 0.00131 AC: 6 AN: 4572

European-Non Finnish (NFE) AF: 0.000783 AC: 746 AN: 953040

Other (OTH) AF: 0.00115 AC: 59 AN: 51376

⚠️ 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: 0.000156 AC: 21 AN: 134284 Hom.: 0 Cov.: 31 AF XY: 0.000139 AC XY: 9 AN XY: 64610

African (AFR) AF: 0.000249 AC: 9 AN: 36126

American (AMR) AF: 0.00 AC: 0 AN: 13540

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4652

South Asian (SAS) AF: 0.00 AC: 0 AN: 4176

European-Finnish (FIN) AF: 0.000129 AC: 1 AN: 7756

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000178 AC: 11 AN: 61902

Other (OTH) AF: 0.00 AC: 0 AN: 1768

Alfa AF: 0.00 Hom.: 5

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Polymerase proofreading-related adenomatous polyposis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.19
Mutation Taster		=99/1	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs369732588; hg19: chr12-133237753;