Variant classification summary

NM_006231.4:c.6111C>T

POLE · NP_006222.2:p.(Ala2037=) · NM_006231.4

GRCh37: chr12:133209275 G>A · GRCh38: chr12:132632689 G>A

Gene: POLE Transcript: NM_006231.4

Final call

BP6 BP7

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.(Ala2037=)

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_006231.4:c.6111C>T is a synonymous POLE variant, NP_006222.2:p.(Ala2037=), and SpliceAI predicts no significant splice impact with a maximum delta score of 0.05, supporting BP7.

2

The variant has been submitted to ClinVar as Likely benign by 4 clinical laboratories and as Benign by 1 clinical laboratory, supporting BP6 under the generic ACMG/AMP framework.

3

Population frequency is low in gnomAD v4.1 at 4.15156e-05 (0.00415%), which is below the BS1 threshold of 0.3% and the BA1 threshold of 1.0%, so benign frequency criteria stronger than supporting are not met.

4

Using the retrieved generic ACMG/AMP final classification combination rules, BP6 plus BP7 constitutes two supporting benign criteria and is consistent with a Likely benign classification.

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	N/A	Synonymous variant NP_006222.2:p.(Ala2037=) is not a predicted loss-of-function allele.	spliceai
PS1	N/A	PS1 is not applicable because this is a synonymous change and does not create an alternate amino-acid substitution matching a known pathogenic variant.	spliceai
PS2	Not assessed	No de novo data were retrieved.
PS3	Not met	No well-established functional study demonstrating a damaging effect for this specific variant was retrieved, and PS3 screening did not identify supporting publications.
PS4	Not met	No case-control enrichment or convincing excess of affected observations over controls was retrieved; COSMIC reported only a single somatic occurrence, which does not support germline PS4.
PM1	Not met	The variant was not identified in a statistically significant hotspot, so location-based pathogenic enrichment was not demonstrated.	oncokb
PM2	Not met	The variant is present in population databases, and no gene-specific rule was retrieved to treat rarity alone as pathogenic evidence for this synonymous change.	gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable because no recessive trans observations were retrieved and POLE constitutional disease in this review context was not framed for PM3 use.
PM4	N/A	PM4 is not applicable because the variant does not change protein length or alter the reading frame.	spliceai
PM5	N/A	PM5 applies to novel missense changes at a residue with a different pathogenic missense variant and is not applicable to a synonymous variant.	spliceai
PM6	Not assessed	No assumed de novo evidence was retrieved.
PP1	Not assessed	No segregation data were retrieved.
PP2	N/A	PP2 is a missense-gene criterion and is not applicable to a synonymous variant.	spliceai
PP3	N/A	PP3 was not applied because the variant is synonymous and computational evidence was more appropriately considered under BP7 rather than as pathogenic support.	spliceai
PP4	Not assessed	No phenotype-specific evidence linking this variant to a highly specific POLE-associated clinical presentation was retrieved.
PP5	N/A	No reputable source classified this variant as pathogenic or likely pathogenic.	clinvar
BA1	Not met	The gnomAD v4.1 total allele frequency is 4.15156e-05 (0.00415%), which is below the benign stand-alone threshold of 1.0%, so BA1 is not met.	gnomad_v4
BS1	Not met	The highest observed population frequency is 9.88099e-05 in gnomAD v4.1 South Asians (0.00988%), which is below the benign strong threshold of 0.3%, so BS1 is not met.	gnomad_v4
BS2	Not assessed	No evidence was retrieved to support observation in healthy adult individuals at a level sufficient for BS2.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional study demonstrating no damaging effect for this specific variant was retrieved, and BS3 screening did not identify supporting publications.
BS4	Not assessed	No segregation data showing lack of cosegregation were retrieved.
BP1	N/A	BP1 is a missense-specific criterion and is not applicable to a synonymous variant.	spliceai
BP2	Not assessed	No phase or co-occurrence data were retrieved.
BP3	N/A	BP3 applies to in-frame indels in repetitive regions and is not applicable to a synonymous single-nucleotide substitution.	spliceai
BP4	N/A	BP4 was not separately applied because the computational evidence for this synonymous variant was considered under BP7.	spliceai
BP5	Not assessed	No alternate molecular explanation for the phenotype was retrieved.
BP6	Met	ClinVar contains benign/likely benign clinical laboratory classifications for this variant (Likely benign from 4 laboratories and Benign from 1 laboratory), supporting BP6 at a supporting level under the generic ACMG/AMP framework.	clinvar
BP7	Met	This is a synonymous variant, NP_006222.2:p.(Ala2037=), and SpliceAI predicts no significant splice impact with a maximum delta score of 0.05, supporting BP7.	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.