12-132675752-G-C

Variant names:

• chr12-132675752-G-C
• rs146639652
• NM_006231.4:c.1089C>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_006231.4(POLE):​c.1089C>G​(p.Asn363Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N363S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.661
• Publications: 7 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 33 uncertain in NM_006231.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 12-132675752-G-C is Pathogenic according to our data. Variant chr12-132675752-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 420748.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4	c.1089C>G	p.Asn363Lys	missense_variant	Exon 11 of 49	ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.1089C>G	p.Asn363Lys	missense_variant	Exon 11 of 49	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Mar 30, 2016

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted POLE c.1089C>G at the cDNA level, p.Asn363Lys (N363K) at the protein level, and results in the change of an Asparagine to a Lysine (AAC>AAG). While this exact variant has not been published in the literature, another missense change impacting the same nucleotide has been published and results in the same amino acid change (POLE c.1089C>A, p.Asn363Lys). POLE Asn363Lys has been reported to segregate with disease in a large family presenting with predominantly colon cancer; other cancers also observed include ovarian, endometrial, pancreatic and gastric (Rohlin 2014). POLE Asn363Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Asparagine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. POLE Asn363Lys occurs at a position that is conserved across species and is located in the exonuclease domain and Exo II and Pol IV motifs (Preston 2010). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider POLE Asn363Lys to be a likely pathogenic variant.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.46	N
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Pathogenic	3.3	M;.
PhyloP100		-0.66
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.4	D;D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.97
ClinPred		1.0	D
GERP RS		-6.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.94
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs146639652; hg19: chr12-133252338;