NM_000314.8:c.143A>C p.(Asn48Thr) is a missense variant in PTEN exon 2. This variant is absent from gnomAD v2.1 and v4.1 (PM2_Supporting).1 Mighell et al. 2018 PTEN saturation mutagenesis functional assay demonstrates a damaging effect with a cumulative fitness score of -3.41 (<= -1.11 threshold, High_conf = True), qualifying for PS3_Moderate per the PTEN VCEP v3.2.0.2 REVEL score of 0.919 exceeds the VCEP PP3 threshold of >0.7 for missense variants.3 PTEN has a low rate of benign missense variation and missense variants are a common mechanism of disease in PHTS (PP2).4 Residue N48 lies outside the VCEP-defined catalytic motifs (90-94, 123-130, 166-168); PM1 is not met.5 No de novo observations, segregation data, proband counting data, or alternate molecular basis cases were available for this variant.6 ClinVar reports this variant as Uncertain significance (2 clinical laboratories, variationID 373667).7 Summary of met criteria: PS3_Moderate + PM2_Supporting + PP2 + PP3. Per the PTEN VCEP final classification framework, this combination does not reach the Likely Pathogenic threshold (Rule11 requires PVS1_Strong/PS1/PS2/PS3/PS4/PM6_Strong/PP1_Strong >=1 AND PVS1_Moderate/PS3_Moderate/PS4_Moderate/PM1/PM4/PM5/PM6/PP1_Moderate ==1; Rule13 requires >=3 Moderate criteria). With 1 Moderate (PS3_Moderate) and 3 Supporting (PM2_Supporting, PP2, PP3), the variant remains classified as Uncertain significance.8
PTEN
Final classification
VUS
PTEN c.143A>C · p.Asn48Thr
PTEN
NM_000314.8:c.143A>C p.(Asn48Thr) is a missense variant in PTEN exon 2.
Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework was evaluated deterministically with applied criteria: PS3 moderate, PM2 supporting, PP2 supporting, PP3 supporting; no rule matched the adjudicated criteria.
Classification rationale
PS3PM2PP2PP3
VUS
PTEN c.143A>C
PS3 + PM2 + PP2 + PP3
→
VUS
Gene diagram
· NM_000314.8 · variants mapped to exon structure
PTEN
NM_000314.8
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 15 assessed
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
✓
PS3
moderate
Pathogenic
Mighell et al. 2018 (PMID: 29706350) massively parallel phosphatase activity assay: N48T cumulative fitness score = -3.41, which is <= the VCEP PS3_Moderate threshold of -1.11 (High_conf = True, Pass SE Filter).
mmc2.xlsx Table S2 row 1046: N48T Cum_score=-3.413875105High_conf=TruePass SE Filter
✓
PM2
supporting
Pathogenic
Absent from gnomAD v2.1 and v4.1, meeting the PTEN VCEP PM2_Supporting threshold of <0.00001 (<0.001%) allele frequency.
gnomAD v2.1: absentgnomAD v4.1: absent
✓
PP2
supporting
Pathogenic
PTEN has a low rate of benign missense variation and missense variants are a common mechanism of disease in PHTS (PTEN Hamartoma Tumor Syndrome), satisfying the VCEP PP2 criterion.
PTEN VCEP v3.2.0 PP2 rule: missense in gene with low benign missense rate and missense as common disease mechanism
✓
PP3
supporting
Pathogenic
REVEL score of 0.919 exceeds the PTEN VCEP PP3 threshold of >0.7 for missense variants, supporting a deleterious effect.
REVEL score 0.919 > 0.7 threshold
Assessed · not applied
Pathogenic
PS1
No previously established pathogenic variant with the same amino acid change (p.Asn48Thr) was identified.
PS2
No de novo observations (confirmed or assumed) were identified for this variant in the available evidence.
PS4
No proband counting data with PTEN specificity scores was available for this variant.
PM1
Residue N48 is outside the PTEN VCEP-defined catalytic motifs (WPD loop 90-94, P-loop 123-130, TI-loop 166-168; NP_000305.3).
PM5
A different missense at the same residue (N48K) is reported in PMID 14675182, but its ACMG/AMP classification is not established and full-text verification was unavailable.
PM6
No assumed de novo observations for this variant were identified in the available evidence.
PP1
No co-segregation data was available for this variant.
Benign
BA1
Variant is absent from gnomAD v2.1 and v4.1; allele frequency of 0 does not exceed the VCEP BA1 threshold of >0.00056 (>0.056%).
BS1
Variant is absent from gnomAD; allele frequency does not fall within the VCEP BS1 range (0.0000043 to 0.00056).
BS2
No homozygous observations of this variant in healthy or PHTS-unaffected individuals were identified; absent from gnomAD.
BS3
Mighell et al.
BS4
No segregation data was available to evaluate lack of segregation in affected family members.
BP2
No observations of this variant in trans with a pathogenic or likely pathogenic PTEN variant, or in cis/phase-unknown with P/LP PTEN variants, were identified.
BP4
REVEL score of 0.919 exceeds the VCEP BP4 threshold of <0.5 for missense variants, indicating computational evidence suggests impact rather than no impact.
BP5
No cases with an alternate molecular basis for disease were identified for this variant, and at least two such cases are required by the VCEP.
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.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
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.
gnomAD Canada 🇨🇦
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). (ClinVarID = 373667)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.919. BayesDel score = 0.224372.
Functional
Likely Oncogenic
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PTEN, a lipid and protein phosphatase, is one of the most frequently mutated genes in cancer.
COSMIC
Cancer hotspots
Somatic evidence
Hotspot
COSMIC
This variant lies in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant lies in a statistically significant hotspot.
Sources & reference links
Triaged references · 5 PMIDs not cited in assessment
14675182 ↗
A novel loss-of-function mutation (N48K) in the PTEN gene in a Spanish patient with Cowden disease.
ONCOKB
21828076 ↗
A comprehensive functional analysis of PTEN mutations: implications in tumor- and autism-related syndromes.
ONCOKB
25527629 ↗
Functionally distinct groups of inherited PTEN mutations in autism and tumour syndromes.
ONCOKB
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR