The PHF6 c.1000G>T (p.Glu334Ter) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, with an observed allele frequency of 0 in both datasets, which is below the 0.1% rarity threshold used to support PM2 at supporting strength.2 PHF6 loss of function is an established disease mechanism, and this nonsense variant is predicted to truncate the protein from 366 to 334 amino acids; however, because the change lies in the last coding exon and removes only the distal C-terminal portion, PVS1 remains for manual review rather than automatic application.3 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00.4
Final classification
VUS
PM2
PHF6
c.1000G>T
p.Glu334Ter
This variant
The PHF6 c.1000G>T (p.Glu334Ter) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.
Generic ACMG/AMP 2015 final-classification combination rules were used because no official VCEP/CSPEC or local custom gene-specific final-classification framework was available.
Classification rationale
PM2
VUS
PHF6 c.1000G>T
PM2
→
VUS
3
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗PMID:39405291
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_001015877.1 · variants mapped to exon structure
PHF6
NM_001015877.1
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 17 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 · 1
Strength
Supporting
Moderate
Strong
Very strong
PM2
supporting
review
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed allele frequency of 0 in both datasets. This is below the non-VCEP rarity threshold of 0.1% and supports PM2 at supporting strength.
Absent from gnomAD v2.1.Absent from gnomAD v4.1.
Assessed · not applied
· 7 not met · 10 not assessed
Pathogenic
PVS1
This variant is a nonsense change, p.(Glu334Ter), in PHF6, and loss of function is an established germline disease mechanism for this gene.
PS2
No confirmed de novo data with parental testing were identified, so this criterion cannot be assessed.
PS3
No well-established functional studies evaluating this specific PHF6 p.(Glu334Ter) variant were identified.
PS4
No case-control or prevalence data showing enrichment of this variant in affected individuals were identified.
PM1
Available evidence does not support that this variant lies in a mutational hotspot or a well-established critical region without benign variation.
PM6
No assumed de novo evidence without confirmed parental testing was identified.
PP1
No segregation data were identified for this variant.
PP4
No phenotype information was provided to determine whether the clinical presentation is highly specific for PHF6-related disease.
PP5
No reputable external pathogenic classification for this exact variant was identified in ClinVar, so PP5 is not supported.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, giving an observed allele frequency of 0.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, giving an observed allele frequency of 0.
BS2
No evidence was identified showing this variant in healthy adult individuals for whom a fully penetrant PHF6-related phenotype would be expected.
BS3
No well-established functional studies demonstrating normal function for this specific PHF6 p.(Glu334Ter) variant were identified.
BS4
No segregation data showing lack of cosegregation with disease were identified.
BP2
No phase information with another pathogenic variant was identified.
BP5
No alternate molecular explanation was identified for the relevant phenotype.
BP6
No reputable external benign classification for this exact variant was identified in ClinVar, so BP6 is not supported.
N/A · 10
PS1 · PM3 · PM4 · PM5 · PP2 · PP3 · BP1 · BP3 · BP4 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Likely Oncogenic
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links