rs1555229333

Positions:

• chr12-132676209-CC-TG

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_006231.4(POLE):​c.910-6_910-5delinsCA variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: POLE NM_006231.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.0250

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 12-132676209-CC-TG is Benign according to our data. Variant chr12-132676209-CC-TG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 473842.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4	c.910-6_910-5delinsCA		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.910-6_910-5delinsCA		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006231.4	ENSP00000322570	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: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 26, 2018

The c.910-6_910-5delGGinsCA intronic variant, located in intron 9 of the POLE gene, results from the deletion of two nucleotides (GG) and the insertion of two nucleotides (CA) at nucleotide positions c.910-6 to c.910-5. These nucleotide positions are poorly conserved in available vertebrate species. Using the Human Splicing Finder (HSF) and MaxEntScan splice site prediction tools, this alteration is not predicted to have any significant effect on this splice acceptor site; however, direct evidence is unavailable (Desmet FO et al. Nucleic Acids Res., 2009 May;37:e67). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 20, 2023

- -

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: rs1555229333; hg19: chr12-133252795;