rs864622698

Variant names:

• chr12-132649801-GC-AA
• rs864622698
• NM_006231.4:c.3670_3671delGCinsTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_006231.4(POLE):​c.3670_3671delGCinsTT​(p.Ala1224Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. The variant is present in control chromosomes in GnomAd MNV project. The variant allele was found at a frequency of 0.000099 in 28 alleles, including 0 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1224S) has been classified as Likely benign.

• Frequency: GnomAD MNV: 𝑓 0.000099 Genomes: not found (cov: 32)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 2.48
• 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: 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4	c.3670_3671delGCinsTT	p.Ala1224Leu	missense_variant		ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.3670_3671delGCinsTT	p.Ala1224Leu	missense_variant		1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

GnomAD MNV AF: 0.0000990 AC: 28 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Jul 09, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis indicates that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Feb 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1224 of the POLE protein (p.Ala1224Leu). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with POLE-related conditions. ClinVar contains an entry for this variant (Variation ID: 220928). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Oct 17, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:2

Jan 12, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ala1224Leu variant in POLE has not been previously reported in individuals with colorectal cancer. This variant is a result of a deletion of 2 nucleotides at positions c.3670 and c.3671 and an insertion of two different nucleotides at these positions and is not predicted to alter the protein reading-frame. This v ariant has been identified in 5/66478 of European chromosomes by the Exome Aggre gation Consortium (ExAC, http://exac.broadinstitute.org, note that the ExAC data base reports this variant as 2 separate substitutions in cis, c.3670G>T [rs36933 8222] and c.3671C>T [rs375208564]). Computational prediction tools and conservat ion analysis suggest that the p.Ala1224Leu variant may not impact the protein, t hough this information is not predictive enough to rule out pathogenicity. In su mmary, the clinical significance of the p.Ala1224Leu variant is uncertain. -

Feb 17, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: POLE c.3670_3671delinsTT (p.Ala1224Leu) results in a non-conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a damaging effect of the variant on protein function. This variant represents a multinucleotide variant that includes a cis arrangement of two variants, namely 12-132649801-G-A (GRCh38), NM_006231.4(POLE):c.3671C>T (p.Ala1224Val) and 12-132649802-C-A (GRCh38), NM_006231.4(POLE):c.3670G>T (p.Ala1224Ser) in gnomAD v4. The variant allele was found at a frequency of 0.00018 in 1614096 control chromosomes, predominantly at a frequency of 0.00023 within the non-Finnish European (NFE) subpopulation in the gnomAD v4 database. Although the observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 16 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLE causing an autosomal dominant susceptibility to Colorectal Cancer (1.4e-05), the available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance in an autosomal recessive (AR) causation (AR-FILS syndrome and AR-IMAGE-I syndrome). To our knowledge, no occurrence of c.3670_3671delinsTT in individuals affected with POLE-associated AD-susceptibility to colorectal cancer/FILS syndrome/IMAGE-I syndrome and no experimental evidence demonstrating its impact on protein function have been reported. The following publication reporting no primary evidence was ascertained in the context of this evaluation (PMID: 31422818). ClinVar contains an entry for this variant (Variation ID: 220928). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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 Uncertain:2

Dec 22, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 25, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Colorectal cancer, susceptibility to, 12 Uncertain:1

Jun 17, 2025

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The POLE c.3670_3671delinsTT (p.Ala1224Leu) change results from deletion of GC and insertion of TT to cause the substitution of the arginine residue for an isoleucine residue at codon 1224. This change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). Algorithms that predict the impact of sequence changes on splicing indicate that this variant does not affect splicing, and to our knowledge functional studies have not been performed. This variant has not been reported as pathogenic in individuals with POLE-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Dec 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3670_3671delGCinsTT variant (also known as p.A1224L), located in coding exon 30 of the POLE gene, results from an in-frame deletion of GC and insertion of TT at nucleotide positions 3670 to 3671. This results in the substitution of the alanine residue for a leucine residue at codon 1224, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5

Splicing

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

Other links and lift over

dbSNP: rs864622698; hg19: chr12-133226387;