rs1555231433

Variant names:

• chr12-132687313-C-G
• rs1555231433
• NM_006231.4:c.3G>C

Your query was ambiguous. Multiple possible variants found:

• chr12-132687313-C-G
• chr12-132687313-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_006231.4(POLE):​c.3G>C​(p.Met1?) variant causes a start lost 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: POLE NM_006231.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.991
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 20 pathogenic variants. Next in-frame start position is after 44 codons. Genomic position: 132681212. Lost 0.019 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4	c.3G>C	p.Met1?	start_lost	Exon 1 of 49	ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.3G>C	p.Met1?	start_lost	Exon 1 of 49	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Dec 26, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M1? variant (also known as c.3G>C), located in coding exon 1 of the POLE gene, results from a G to C substitution at nucleotide position 3. Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame; however there is an alternate in-frame methionine 43 amino acids from the initiation site. As neither this specific alteration nor loss-of-function as a mechanism of pathogenicity have been well-described in the POLE gene, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.041	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Benign	-0.99	T
PhyloP100		0.99
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.0	B;B
Vest4		0.71
MutPred		0.88		Gain of catalytic residue at R4 (P = 0.0169);Gain of catalytic residue at R4 (P = 0.0169);
MVP		0.32
ClinPred		0.53	D
GERP RS		2.6
PromoterAI		-0.028	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.61
Mutation Taster		=17/183	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1555231433; hg19: chr12-133263899;