c.368A>G (p.His123Arg) is a missense variant in exon 5 of PTEN, within the phosphatase catalytic motif (residues 123-130).1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2_Supporting under PTEN VCEP rules.2 His123 is located within the VCEP-defined catalytic motif, meeting PM1_Moderate.3 The variant has been classified as Pathogenic by the ClinGen PTEN Variant Curation Expert Panel (ClinVar SCV000863477, reviewed by expert panel).4 In the Mighell et al. 2018 (PMID:29706350) saturation mutagenesis phosphatase activity assay, H123R has a cumulative fitness score of -3.83 (High_conf = True), meeting the PTEN VCEP threshold for PS3_Moderate (Cum_score <= -1.11).5 The ClinGen PTEN VCEP applied PM6_Moderate, noting an assumed de novo occurrence (parentage unconfirmed) in a patient with Cowden syndrome (Nelen et al. 1999, PMID:10234502).6 Computational evidence supports pathogenicity: REVEL score 0.985 meets PP3_Supporting; PTEN's low rate of benign missense variation supports PP2_Supporting.7 The ClinGen PTEN VCEP classification as Pathogenic supports PP5_Supporting, applied per user directive to override VCEP Not Applicable when expert panel classification exists.8
PTEN
Final classification
Likely Pathogenic
PTEN c.368A>G · p.His123Arg
PTEN
c.368A>G (p.His123Arg) is a missense variant in exon 5 of PTEN, within the phosphatase catalytic motif (residues 123-130).
Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework: matched Rule13 (Pathogenic.Moderate >=3) with applied criteria: PS3 moderate, PM1 moderate, PM2 supporting, PM6 moderate, PP2 supporting, PP3 supporting, PP5 supporting; maps to Likely Pathogenic.
Classification rationale
PS3PM1PM2PM6PP2PP3PP5
Likely Pathogenic
PTEN c.368A>G
PS3 + PM1 + PM2 + PM6 + PP2 + PP3 + PP5
→
Likely Pathogenic
Gene diagram
· NM_000314.8 · variants mapped to exon structure
PTEN
NM_000314.8
Fetching transcript structure from UCSC…
Applied criteria · 7 applied · 13 assessed
Applied · 7
Strength
Supporting
Moderate
Strong
Very strong
✓
PS3
moderate
Pathogenic
PTEN H123R (His123Arg) has a cumulative fitness score (Cum_score) of -3.83 in the Mighell et al. 2018 (PMID:29706350) saturation mutagenesis phosphatase activity assay. This score is ≤ -1.11, meeting the PTEN VCEP threshold for PS3_Moderate. The measurement is high-confidence (High_conf = True, Pass SE Filter).
Mighell et al. 2018 massively parallel phosphatase activity assay: H123R Cum_score = -3.834High_conf = True.
✓
PM1
moderate
Pathogenic
Residue His123 is located within the PTEN phosphatase catalytic motif defined by the VCEP as residues 123-130 (NP_000305.3). This meets the PTEN VCEP PM1_Moderate criterion for missense variants located in a critical functional domain.
His123 is within the VCEP-defined catalytic motif residues 123-130 of the phosphatase domain.
✓
PM2
supporting
Pathogenic
c.368A>G is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Per PTEN VCEP rules, absence from large sequenced population databases (< 0.001% allele frequency) meets PM2_Supporting.
Absent from gnomAD v2.1 (0 alleles)gnomAD v4.1 (0 alleles)and gnomAD-Canada v1.0 (0 alleles).
✓
PM6
moderate
Pathogenic
The ClinGen PTEN Variant Curation Expert Panel (SCV000863477) explicitly applied PM6 at the Moderate level, noting 'assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history.' This expert panel determination is followed directly. The de novo observation is referenced to Nelen et al. 1999 (PMID:10234502).
ClinGen PTEN VCEP applied PM6_Moderate: assumed de novo in a Cowden syndrome patientparentage not confirmed (Nelen et al. 1999).
✓
PP2
supporting
Pathogenic
PTEN is a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease. Per PTEN VCEP rules, PP2_Supporting applies to missense variants.
PTEN has low benign missense variation ratemissense variants are a common disease mechanism.
✓
PP3
supporting
Pathogenic
REVEL score is 0.985, which exceeds the PTEN VCEP PP3 threshold of > 0.7 for missense variants. SpliceAI predicts no splicing impact (max delta = 0.01), consistent with a missense mechanism rather than splicing defect. BayesDel score of 0.61462 also supports a deleterious prediction.
REVEL = 0.985 (> 0.7 threshold)BayesDel = 0.615SpliceAI max delta = 0.01 (no splicing impact).
Assessed · not applied
Pathogenic
PS1
PS1 requires the same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
PS2
ClinVar submissions (SCV004103762, SCV000617322) and the ClinGen PTEN VCEP (SCV000863477) reference a de novo occurrence in Nelen et al.
PS4
PS4 requires variant-specific proband counts with phenotype specificity scores.
PM5
PM5 requires a different pathogenic or likely pathogenic missense variant at the same amino acid residue (His123).
PP1
No co-segregation data were available for this variant.
Benign
BA1
c.368A>G is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
c.368A>G is absent from gnomAD.
BS2
BS2 requires observation in the homozygous state in a healthy or PHTS-unaffected individual.
BS3
PTEN H123R has a Cum_score of -3.83 in the Mighell et al.
BS4
BS4 requires lack of segregation in affected family members (two or more families for Strong, one family for Supporting).
BP2
BP2 requires observation in trans with a pathogenic/likely pathogenic PTEN variant or at least three observations in cis/phase unknown.
BP4
BP4 requires multiple lines of computational evidence suggesting no impact on the gene product.
BP5
BP5 requires a variant found in a case with an alternate molecular basis for disease where the other gene/disorder is highly penetrant and the patient's history does not overlap with PTEN.
N/A · 8
PVS1 · PM3 · PM4 · PP4 · BP1 · BP3 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
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 Pathogenic (4 clinical laboratories) and as Pathogenic by Clingen PTEN Variant Curation Expert Panel, Clingen (expert panel). (ClinVarID = 7816)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.985. BayesDel score = 0.61462.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Hotspot
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV64309701, n = 4 times).
Hotspots
This variant lies in a statistically significant hotspot.
Sources & reference links
9Sources
Triaged references · 8 PMIDs not cited in assessment
10555148 ↗
Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association.
CLINVAR
10772829 ↗
Cell cycle arrest by the PTEN tumor suppressor is target cell specific and may require protein phosphatase activity.
CLINVAR
16619501 ↗
Tumour suppressor PTEN regulates cell cycle and protein kinase B/Akt pathway in breast cancer cells.
CLINVAR
21828076 ↗
A comprehensive functional analysis of PTEN mutations: implications in tumor- and autism-related syndromes.
CLINVAR
23161105 ↗
A new insight into structural and functional impact of single-nucleotide polymorphisms in PTEN gene.
CLINVAR
25527629 ↗
Functionally distinct groups of inherited PTEN mutations in autism and tumour syndromes.
CLINVAR
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
26800850 ↗
Prediction of functionally significant single nucleotide polymorphisms in PTEN tumor suppressor gene: An in silico approach.
CLINVAR