NM_000314.8:c.745G>A (NP_000305.3:p.(Val249Met), p.(V249M)) is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PTEN Expert Panel PM2 threshold of <0.00001 (0.001%) and supports PM2_Supporting.1 As a PTEN missense variant, p.(Val249Met) supports PP2 because missense variation is an established disease mechanism for this gene in the PTEN Expert Panel framework.2 In the Mighell PTEN phosphatase assay, p.Val249Met has a cumulative score of -0.30689816, which is above the PS3_Moderate threshold of <= -1.11 and below the BS3 threshold of >0, so the available PTEN-specific functional data do not support either PS3 or BS3.3 The REVEL score is 0.679, which is below the PTEN PP3 threshold of >0.7 and above the PTEN BP4 threshold of <0.5, so computational missense evidence does not support either criterion. With PM2_Supporting and PP2 met, and no additional PTEN Expert Panel pathogenic or benign criteria satisfied, PTEN p.(Val249Met) is classified as a variant of uncertain significance.4
Final classification
Uncertain significance
PM2PP2
PTEN
c.745G>A
p.Val249Met
This variant
NM_000314.8:c.745G>A (NP_000305.3:p.(Val249Met), p.(V249M)) is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PTEN Expert Panel PM2 threshold of <0.00001 (0.001%) and supports PM2_Supporting.
ACMG/AMP classification using ClinGen PTEN Expert Panel Specifications v3.2.0
Classification rationale
PM2PP2
Uncertain significance
PTEN c.745G>A
PM2 + PP2
→
Uncertain significance
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_000314.8 · variants mapped to exon structure
PTEN
NM_000314.8
Fetching transcript structure from UCSC…
Applied criteria · 2 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 · 2
Strength
Supporting
Moderate
Strong
Very strong
PM2
Supporting
review
Pathogenic
The variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which is below the PTEN EP PM2 threshold of <0.00001 (0.001%) for population data and supports PM2_Supporting.
gnomAD v2.1 absentgnomAD v4.1 absent
PP2
Supporting
review
Pathogenic
This is a PTEN missense variant, and the PTEN Expert Panel retains PP2 for missense changes in a gene where missense variation is a recognized disease mechanism.
Missense consequence p.(Val249Met)
Assessed · not applied
· 7 not met · 10 not assessed
Pathogenic
PS1
No workspace evidence established a previously classified pathogenic PTEN variant producing the same amino-acid change p.Val249Met.
PS2
No confirmed de novo data were provided.
PS3
In PTEN supplementary Table S2 from Mighell et al., p.Val249Met (V249M) has Cum_score -0.30689816, which is above the PTEN EP PS3_Moderate threshold of <= -1.11; no splicing assay showing damaging impact was provided.
PS4
The workspace did not provide qualifying PTEN phenotype-specific proband counts, specificity scores, or case-control enrichment data for this variant.
PM1
PTEN PM1 is restricted to catalytic motif residues 90-94, 123-130, and 166-168; Val249 lies outside these defined motifs.
PM5
No curated evidence in the workspace established a different pathogenic or likely pathogenic missense change at PTEN codon 249 with a qualifying BLOSUM62 comparison.
PM6
No assumed de novo observations were provided.
PP1
No segregation data were provided to count informative meioses.
PP3
For PTEN missense variants, PP3 requires REVEL >0.7; the assembled REVEL score is 0.679, so this threshold is not reached.
Benign
BA1
BA1 requires gnomAD filtering allele frequency >0.00056 (0.056%); this variant is absent from gnomAD v2.1 and v4.1.
BS1
BS1 requires a gnomAD filtering allele frequency from 0.000043 to 0.00056 for strong strength or from 0.0000043 to 0.000043 for supporting strength; this variant is absent from gnomAD v2.1 and v4.1.
BS2
No homozygous observations in healthy or PHTS-unaffected individuals were provided.
BS3
In the PTEN Mighell assay, BS3_Supporting requires phosphatase activity >0; p.Val249Met has Cum_score -0.30689816, so it does not meet the benign functional threshold, and no splicing assay showing no effect was provided.
BS4
No lack-of-segregation evidence was provided.
BP2
No phase data with a pathogenic or likely pathogenic PTEN variant were provided.
BP4
For PTEN missense variants, BP4 requires REVEL <0.5; the assembled REVEL score is 0.679, so the benign computational threshold is not met.
BP5
No evidence of an alternate highly penetrant molecular diagnosis with non-overlapping PTEN phenotype was provided.
N/A · 9
PVS1 · PM3 · PM4 · PP4 · PP5 · BP1 · BP3 · BP6 · 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.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).
Functional
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: PTEN, a lipid and protein phosphatase, is one of the most frequently mutated genes in cancer.
COSMIC
Cancer hotspots
Somatic evidence
COSMIC
This variant has previously been reported in somatic cancers (COSMIC; COSV64304069, n = 1 times).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links