chr12-132634277-G-GTTGGATTCCTCCACT

Position:

• chr12-132634277-G-GTTGGATTCCTCCACT

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_006231.4(POLE):​c.5912_5913insAGTGGAGGAATCCAA​(p.Ser1970_Asn1971insLysValGluGluSer) variant causes a inframe insertion 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLE NM_006231.4 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.932

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_006231.4.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4	c.5912_5913insAGTGGAGGAATCCAA	p.Ser1970_Asn1971insLysValGluGluSer	inframe_insertion	43/49	ENST00000320574.10	NP_006222.2
POLE	XM_011534795.4	c.5912_5913insAGTGGAGGAATCCAA	p.Ser1970_Asn1971insLysValGluGluSer	inframe_insertion	43/48		XP_011533097.1
POLE	XM_011534797.4	c.4991_4992insAGTGGAGGAATCCAA	p.Ser1663_Asn1664insLysValGluGluSer	inframe_insertion	35/40		XP_011533099.1
POLE	XM_011534802.4	c.2900_2901insAGTGGAGGAATCCAA	p.Ser966_Asn967insLysValGluGluSer	inframe_insertion	19/24		XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.5912_5913insAGTGGAGGAATCCAA	p.Ser1970_Asn1971insLysValGluGluSer	inframe_insertion	43/49	1	NM_006231.4	ENSP00000322570	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 06, 2016

In summary, this variant is a novel in-frame insertion with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a POLE-related disease. This sequence change inserts 15 nucleotides in exon 43 of the POLE mRNA (c.5912_5913insAGTGGAGGAATCCAA). This leads to the insertion of 5 amino acid residues in the POLE protein (p.Ser1970_Asn1971insLysValGluGluSer) but otherwise preserves the integrity of the reading frame. -

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: rs878854887; hg19: chr12-133210863;