rs1555301223

chr12-132626209-GGTCTC-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_006231.4(POLE):c.6434_6438del(p.Arg2145ProfsTer9) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R2145R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: POLE NM_006231.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.75

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 12-132626209-GGTCTC-G is Pathogenic according to our data. Variant chr12-132626209-GGTCTC-G is described in ClinVar as [Pathogenic]. Clinvar id is 540827.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLE	NM_006231.4	c.6434_6438del	p.Arg2145ProfsTer9	frameshift_variant	46/49	ENST00000320574.10
POLE	XM_011534795.4	c.6434_6438del	p.Arg2145ProfsTer9	frameshift_variant	46/48
POLE	XM_011534797.4	c.5513_5517del	p.Arg1838ProfsTer9	frameshift_variant	38/40
POLE	XM_011534802.4	c.3422_3426del	p.Arg1141ProfsTer9	frameshift_variant	22/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLE	ENST00000320574.10	c.6434_6438del	p.Arg2145ProfsTer9	frameshift_variant	46/49	1	NM_006231.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 11, 2022

This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg2145Profs*9) in the POLE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POLE are known to be pathogenic (PMID: 23230001, 25948378, 30503519). 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: 540827). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555301223; hg19: chr12-133202795;