NM_006231.4:c.4006-15C>T

POLE · NP_006222.2:p.? · NM_006231.4

GRCh37: chr12:133225673 G>A · GRCh38: chr12:132649087 G>A

Gene: POLE Transcript: NM_006231.4

Final call

VUS

PM2 BP4

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

The variant is very rare in population databases, with gnomAD v2.1 total AF 2.04127e-05 (0.00204%) and grpmax FAF 2.326e-05, which are below the generic PM2 rarity threshold of 0.1%.

gnomAD v4.1 likewise shows a total AF of 1.44198e-05 (0.00144%) and grpmax FAF 3.005e-05, which remains below the generic PM2 rarity threshold of 0.1% and confirms that the variant is uncommon in the general population.

SpliceAI predicts minimal splicing effect, with a maximum delta score of 0.03, which is below the splice-impact threshold of 0.2 and supports BP4.

ClinVar contains a likely benign classification for this variant with single-submitter review status, which is concordant with a benign leaning but is not used as stand-alone classification evidence.

Because the available data provide one supporting pathogenic criterion for rarity and one supporting benign criterion for computational evidence against splice disruption, NM_006231.4:c.4006-15C>T is classified as a variant of uncertain significance.

Final determination:

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not met	NM_006231.4:c.4006-15C>T is an intronic variant 15 bases upstream of exon 32, and SpliceAI shows a maximum delta score of 0.03, which is below the splicing concern threshold of 0.2; no evidence in the case file demonstrates a null effect or predicted exon skipping/cryptic splice creation sufficient for PVS1.	spliceai
PS1	Not assessed	PS1 requires the same amino acid change as an established pathogenic variant, and no such matched protein-altering comparison is relevant for this intronic variant in the available record.
PS2	Not assessed	No de novo data with confirmed maternity and paternity are provided.
PS3	Not assessed	No functional assay demonstrating a damaging effect on POLE splicing or function is provided.
PS4	Not assessed	No case-control enrichment, case series, or prevalence comparison supporting increased occurrence in affected individuals is provided.
PM1	Not assessed	No evidence places this intronic position in a defined mutational hot spot or critical functional domain without benign variation.	oncokb
PM2	Met	The variant is rare in population databases: gnomAD v2.1 total AF is 2.04127e-05 (0.00204%) with grpmax FAF 2.326e-05, and gnomAD v4.1 total AF is 1.44198e-05 (0.00144%) with grpmax FAF 3.005e-05; these values are below the generic PM2 rarity threshold of 0.1%.	gnomad_v2 gnomad_v4
PM3	N/A	PM3 is a recessive-phase criterion, and no recessive POLE context is established for this case.
PM4	N/A	PM4 applies to protein length changes, which are not relevant to this intronic noncoding variant.
PM5	N/A	PM5 applies to novel missense changes at the same residue and is not relevant to this intronic variant.
PM6	Not assessed	No assumed de novo occurrence data are provided.
PP1	Not assessed	No segregation data are provided.
PP2	N/A	PP2 is a missense-specific criterion and is not relevant to this intronic variant.
PP3	Not met	Computational evidence does not support a deleterious splicing effect because the SpliceAI maximum delta score is 0.03, which is below the commonly used splice-impact threshold of 0.2.	spliceai
PP4	Not assessed	No phenotype, tumor spectrum, or family history data specific enough to POLE-associated disease are provided.
PP5	Not assessed	Although ClinVar contains a classification, PP5 is not applied here as stand-alone evidence.	clinvar
BA1	Not met	Benign stand-alone frequency is not met because gnomAD v4.1 total AF is 1.44198e-05 (0.00144%) and gnomAD v2.1 total AF is 2.04127e-05 (0.00204%), both well below the generic BA1 threshold of 1%.	gnomad_v2 gnomad_v4
BS1	Not met	Benign strong frequency is not met because gnomAD v4.1 total AF is 1.44198e-05 (0.00144%) and gnomAD v2.1 total AF is 2.04127e-05 (0.00204%), both below the generic BS1 threshold of 0.3%.	gnomad_v2 gnomad_v4
BS2	Not assessed	No data demonstrate observation in healthy adult individuals at a level sufficient for BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	No functional assay demonstrating a benign effect is provided.
BS4	Not assessed	No nonsegregation data are provided.
BP1	N/A	BP1 is a missense-specific criterion and is not relevant to this intronic variant.
BP2	Not assessed	No phase data with another pathogenic variant are provided.
BP3	N/A	BP3 applies to in-frame indels in repetitive regions and is not relevant to this intronic SNV.
BP4	Met	Computational evidence supports no impact on splicing because the SpliceAI maximum delta score is 0.03, which is below the splice-impact threshold of 0.2.	spliceai
BP5	Not assessed	No alternate molecular explanation or case-level data are provided to support BP5.
BP6	Not assessed	ClinVar lists this variant as likely benign with single-submitter review status, but BP6 is not used here as stand-alone evidence.	clinvar
BP7	Not assessed	The intronic position and low SpliceAI score are compatible with a benign splicing interpretation, but the available record does not provide the additional conservation assessment needed to apply BP7 confidently.	spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.