NM_006231.4:c.4952+17_4952+19dupCGT

Variant names:

• chr12-132642486-A-AACG
• rs571641918
• NM_006231.4:c.4952+17_4952+19dupCGT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_006231.4(POLE):​c.4952+17_4952+19dupCGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00818 in 1,607,440 control chromosomes in the GnomAD database, including 70 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0085 (65 hom.)
• Consequence: POLE NM_006231.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.00100
• Publications: 0 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 -16 ACMG points.

• BP6: Variant 12-132642486-A-AACG is Benign according to our data. Variant chr12-132642486-A-AACG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 371873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00533 (811/152200) while in subpopulation NFE AF = 0.00893 (607/67980). AF 95% confidence interval is 0.00834. There are 5 homozygotes in GnomAd4. There are 383 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR,AD gene

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.4952+17_4952+19dupCGT		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.4952+19_4952+20insCGT		intron	N/A	ENSP00000322570.5	Q07864
	POLE	ENST00000535270.5	TSL:1	c.4871+19_4871+20insCGT		intron	N/A	ENSP00000445753.1	F5H1D6
	POLE	ENST00000537064.5	TSL:1	n.*4703+19_*4703+20insCGT		intron	N/A	ENSP00000442578.1	F5H7E4

Frequencies

GnomAD3 genomes AF: 0.00533 AC: 811 AN: 152082 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00434

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00893

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00565 AC: 1407 AN: 249166 AF XY: 0.00564

Gnomad AFR exome AF: 0.000989

Gnomad AMR exome AF: 0.00267

Gnomad ASJ exome AF: 0.00787

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00374

Gnomad NFE exome AF: 0.00987

Gnomad OTH exome AF: 0.00541

GnomAD4 exome AF: 0.00848 AC: 12335 AN: 1455240 Hom.: 65 Cov.: 34 AF XY: 0.00817 AC XY: 5908 AN XY: 722832

African (AFR) AF: 0.000839 AC: 28 AN: 33370

American (AMR) AF: 0.00258 AC: 115 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.00710 AC: 185 AN: 26064

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39538

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86162

European-Finnish (FIN) AF: 0.00479 AC: 253 AN: 52842

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5748

European-Non Finnish (NFE) AF: 0.0103 AC: 11379 AN: 1106782

Other (OTH) AF: 0.00619 AC: 372 AN: 60100

GnomAD4 genome AF: 0.00533 AC: 811 AN: 152200 Hom.: 5 Cov.: 33 AF XY: 0.00515 AC XY: 383 AN XY: 74384

African (AFR) AF: 0.00178 AC: 74 AN: 41550

American (AMR) AF: 0.00307 AC: 47 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00864 AC: 30 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00434 AC: 46 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00893 AC: 607 AN: 67980

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00714 Hom.: 0

Bravo AF: 0.00532

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	1	Colorectal cancer, susceptibility to, 12 (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.0010
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs571641918; hg19: chr12-133219072;