rs878854893

Variant names:

• chr12-132626143-G-A
• rs878854893
• NM_006231.4:c.6505C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-132626143-G-A
• chr12-132626143-G-C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_006231.4(POLE):​c.6505C>T​(p.Leu2169Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.00000413 in 1,454,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L2169L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: POLE NM_006231.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.77
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 12-132626143-G-A is Benign according to our data. Variant chr12-132626143-G-A is described in CliVar as Likely_benign. Clinvar id is 240599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132626143-G-A is described in CliVar as Likely_benign. Clinvar id is 240599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132626143-G-A is described in CliVar as Likely_benign. Clinvar id is 240599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132626143-G-A is described in CliVar as Likely_benign. Clinvar id is 240599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4	c.6505C>T	p.Leu2169Leu	synonymous_variant	Exon 46 of 49	ENST00000320574.10	NP_006222.2
POLE	XM_011534795.4	c.6505C>T	p.Leu2169Leu	synonymous_variant	Exon 46 of 48		XP_011533097.1
POLE	XM_011534797.4	c.5584C>T	p.Leu1862Leu	synonymous_variant	Exon 38 of 40		XP_011533099.1
POLE	XM_011534802.4	c.3493C>T	p.Leu1165Leu	synonymous_variant	Exon 22 of 24		XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.6505C>T	p.Leu2169Leu	synonymous_variant	Exon 46 of 49	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000413 AC: 6 AN: 1454422 Hom.: 0 Cov.: 32 AF XY: 0.00000415 AC XY: 3 AN XY: 722916

African (AFR) AF: 0.00 AC: 0 AN: 33254

American (AMR) AF: 0.00 AC: 0 AN: 43568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26000

East Asian (EAS) AF: 0.00 AC: 0 AN: 39404

South Asian (SAS) AF: 0.00 AC: 0 AN: 85190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52796

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5508

European-Non Finnish (NFE) AF: 0.00000451 AC: 5 AN: 1108588

Other (OTH) AF: 0.0000166 AC: 1 AN: 60114

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polymerase proofreading-related adenomatous polyposis Benign:1

Feb 16, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Dec 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

May 06, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	4.0
DANN	Benign	0.83
PhyloP100		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs878854893; hg19: chr12-133202729;