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 BP7.1 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.2 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.3 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.4
Final classification
Likely benign
BP6BP7
POLE
c.6111C>T
p.Ala2037=
This variant
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.
Generic ACMG/AMP 2015 fallback using the retrieved generic_acmg_combination_rules; two supporting benign criteria were applied (BP6 and BP7), which matches the generic ACMG/AMP Likely Benign combination rule.
Classification rationale
BP6BP7
Likely benign
POLE c.6111C>T
BP6 + BP7
→
Likely benign
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_006231.4 · variants mapped to exon structure
POLE
NM_006231.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 15 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
BP6
supporting
Benign
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 variation 391387: Likely benign from 4 clinical laboratories and Benign from 1 clinical laboratory; review status 'criteria provided, single submitter'.
BP7
supporting
Benign
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.
Protein consequence NP_006222.2:p.(Ala2037=).SpliceAI max delta score 0.05 with evidence sentence 'no significant splice impact'.
Assessed · not applied
· 7 not met · 8 not assessed
Pathogenic
PS2
No de novo data were retrieved.
PS3
No well-established functional study demonstrating a damaging effect for this specific variant was retrieved, and PS3 screening did not identify supporting publications.
PS4
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
The variant was not identified in a statistically significant hotspot, so location-based pathogenic enrichment was not demonstrated.
PM2
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.
PM6
No assumed de novo evidence was retrieved.
PP1
No segregation data were retrieved.
PP4
No phenotype-specific evidence linking this variant to a highly specific POLE-associated clinical presentation was retrieved.
Benign
BA1
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.
BS1
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.
BS2
No evidence was retrieved to support observation in healthy adult individuals at a level sufficient for BS2.
BS3
No well-established functional study demonstrating no damaging effect for this specific variant was retrieved, and BS3 screening did not identify supporting publications.
BS4
No segregation data showing lack of cosegregation were retrieved.
BP2
No phase or co-occurrence data were retrieved.
BP5
No alternate molecular explanation for the phenotype was retrieved.
N/A · 11
PVS1 · PS1 · PM3 · PM4 · PM5 · PP2 · PP3 · PP5 · BP1 · BP3 · BP4
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 4.15156e-05; MAF= 0.00415%, 67/1613852 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 9.88099e-05; MAF= 0.00988%, 9/91084 alleles, homozygotes = 0); grpmax FAF= 6.806e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 4.97368e-05; MAF= 0.00497%, 14/281482 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000228698; MAF= 0.02287%, 7/30608 alleles, homozygotes = 0); grpmax FAF= 0.00010658.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0042%
· 67 / 1,613,852
0 hom · FAF 0.0068%
0 hom · FAF 0.0068%
South Asian 9 / 91,084 |
0.0099% |
European (non-Finnish) 56 / 1,179,988 |
0.0047% |
Admixed American 1 / 60,002 |
0.0017% |
Remaining individuals 1 / 62,482 |
0.0016% |
+ 6 not observed (European (Finnish), Middle Eastern, Ashkenazi Jewish, East Asian, African/African American, Amish)
gnomAD v2.1
0.005%
· 14 / 281,482
0 hom · FAF 0.011%
0 hom · FAF 0.011%
South Asian 7 / 30,608 |
0.023% |
European (non-Finnish) 6 / 128,300 |
0.0047% |
Admixed American 1 / 35,404 |
0.0028% |
+ 5 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)
ClinVar
This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Benign (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05).
Functional
OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).
COSMIC
Cancer hotspots
Somatic evidence
COSMIC
This variant has previously been reported in somatic cancers (COSMIC; COSV107342250, n = 1 times).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links