About PPP2R1A
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PPP2R1A c.536C>G, p.(Pro179Arg)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PS3Strong
PS3 · strong
P179R was directly tested in PMID:31142515 via X-ray crystallography (PDB 6EF4, 3.4Å resolution), co-immunoprecipitation, phosphatase activity assays, molecular dynamics simulations, and patient-derived endometrial carcinoma models (UT89, UT42). P179R disrupts PP2A holoenzyme assembly by altering Aα-subunit conformation, near-completely abolishes catalytic C-subunit binding, promotes proteasome-mediated C-subunit degradation, and reduces PP2A phosphatase activity. Restoration of wild-type Aα in P179R-mutant patient-derived cells suppresses tumorigenic features in xenograft assays. The functional effect is unequivocal and directly demonstrated for the exact variant.
PM1Moderate
PM1 · moderate
Residue P179 is a statistically significant mutational hotspot (cancerhotspots.org) and lies within HEAT domain 5 of the PP2A Aα scaffolding subunit, a critical functional domain for PP2A holoenzyme assembly. PMID:31142515 identifies P179 as the most recurrent PPP2R1A mutation site in high-grade endometrial carcinoma (48 of 51 reported P179 mutations are P179R). No benign variation has been reported at this residue in population databases.
PM2Moderate
PM2 · moderate
NM_014225.5:c.536C>G is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), meeting the PM2 threshold of <0.1% allele frequency in large population databases.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 strong, PM1 moderate, PM2 moderate; combination = 1 strong + 2 moderate, which maps to Likely Pathogenic.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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
92 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV59042232, n = 92 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
27 criteria with recorded statuses: 3 met · 21 not met · 0 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_014225.5:c.536C>G (p.Pro179Arg) in PPP2R1A is classified as Likely Pathogenic per ACMG/AMP 2015 generic framework.
PS3 (Strong): Direct functional characterization of P179R via X-ray crystallography, co-immunoprecipitation, phosphatase assays, and patient-derived tumor models demonstrates unequivocal disruption of PP2A holoenzyme assembly, loss of catalytic subunit binding, and tumorigenic potential.
PM1 (Moderate): Residue P179 is a statistically significant mutational hotspot (cancerhotspots.org) within HEAT domain 5, a critical functional domain of the PP2A Aα scaffolding subunit.
PM2 (Moderate): Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (allele frequency <0.1%).
Combined evidence (1 Strong + 2 Moderate) meets the ACMG/AMP 2015 threshold for Likely Pathogenic classification.
This variant has been observed somatically in 92 cancer specimens (COSMIC COSV59042232) and is the most recurrent PPP2R1A mutation in high-grade endometrial carcinoma, though germline clinical classification is based on the functional and population evidence cited above.
No criteria match.
Met · 3
PS3 StrongP179R was directly tested in PMID:31142515 via X-ray crystallography (PDB 6EF4, 3.4Å resolution), co-immunoprecipitation, phosphatase activity assays, molecular dynamics simulations, and patient-derived endometrial carcinoma models (UT89, UT42). P179R disrupts PP2A holoenzyme assembly by altering Aα-subunit conformation, near-completely abolishes catalytic C-subunit binding, promotes proteasome-mediated C-subunit degradation, and reduces PP2A phosphatase activity. Restoration of wild-type Aα in P179R-mutant patient-derived cells suppresses tumorigenic features in xenograft assays. The functional effect is unequivocal and directly demonstrated for the exact variant. Details ▾Hide ▴
Evidence considered
- Crystal structure of P179R-Aα at 3.4Å resolution (PDB 6EF4) shows altered conformation vs wild-type.
- Co-IP demonstrates near-complete loss of catalytic C-subunit binding and significant loss of B-subunit binding.
- Molecular dynamics simulations confirm conformational shift favoring 'closed' donut shape that excludes C-subunit.
- Phosphatase activity is reduced in P179R-expressing cells.
- Restoration of wild-type Aα in P179R-mutant patient-derived UT42 cells suppresses tumorigenesis in xenograft models.
- PMID:40604275 independently confirms functional relevance of P179R in ovarian cancer
- showing increased CAR-T sensitivity.
Sources
PM1 ModerateResidue P179 is a statistically significant mutational hotspot (cancerhotspots.org) and lies within HEAT domain 5 of the PP2A Aα scaffolding subunit, a critical functional domain for PP2A holoenzyme assembly. PMID:31142515 identifies P179 as the most recurrent PPP2R1A mutation site in high-grade endometrial carcinoma (48 of 51 reported P179 mutations are P179R). No benign variation has been reported at this residue in population databases. Details ▾Hide ▴
Evidence considered
- P179 is a statistically significant hotspot residue (cancerhotspots.org).
- PMID:31142515: P179 is in HEAT domain 5 of PP2A Aα
- 48 of 51 P179 mutations are P179R
- P179 is the most recurrent PPP2R1A mutation site in endometrial carcinoma.
Sources
PM2 ModerateNM_014225.5:c.536C>G is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), meeting the PM2 threshold of <0.1% allele frequency in large population databases. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (AF=null).
- Absent from gnomAD v4.1 (AF=null).
- Absent from gnomAD-Canada v1.0 (AF=0.0).
Sources
Not met · 21 · evaluated, threshold not reached
PVS1 NM_014225.5:c.536C>G is a missense variant (p.Pro179Arg) and does not fall into null-variant categories (nonsense, frameshift, or canonical ±1,2 splice consensus) required for generic PVS1 application per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense variant
- variant_bucket='other'
- apply_generic_pvs1_framework=false.
Sources
PS1 No evidence of an alternate nucleotide change at codon 179 producing the same p.Pro179Arg substitution that has been classified as pathogenic. Details ▾Hide ▴
Still missing
- No alternate nucleotide variant producing p.Pro179Arg identified.
PS2 No de novo observation with confirmed maternity and paternity has been reported for NM_014225.5:c.536C>G (p.Pro179Arg). Details ▾Hide ▴
Still missing
- No de novo data for this variant.
PS4 No case-control prevalence data comparing affected individuals to controls is available for this variant. Details ▾Hide ▴
Still missing
- No case-control data.
PM5 No same-residue (P179) comparator variant with a pathogenic classification in ClinVar was identified; automated PM5 candidate harvesting yielded no candidates. Other P179 variants (P179L, P179T, P179H) have been reported in the literature as somatic mutations but lack germline pathogenic classification in ClinVar. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: 0 same-residue pathogenic candidates in ClinVar.
Still missing
- No germline pathogenic comparator at residue P179 in ClinVar.
Sources
pm5_candidates
PM6 No de novo observation (without confirmed maternity/paternity) has been reported for NM_014225.5:c.536C>G. Details ▾Hide ▴
Still missing
- No de novo reports for this variant.
PP1 No co-segregation data with disease in multiple affected family members is available for this variant. Details ▾Hide ▴
Still missing
- No co-segregation data.
PP2 No gene-level missense constraint metric (e.g., gnomAD missense Z-score or HCI prior probability) is available to establish that PPP2R1A has a low rate of benign missense variation. HCI prior lookup returned 'gene_not_supported'. Details ▾Hide ▴
Evidence considered
- HCI prior: not found (gene_not_supported).
- No gnomAD missense constraint Z-score available.
Still missing
- No gene-level missense constraint metric available.
PP3 Computational predictors do not support a deleterious effect. REVEL score is 0.386 (below 0.5 threshold), BayesDel score is 0.123, and SpliceAI max delta is 0.01 (no splicing impact). Multiple lines of computational evidence do not support PP3. Details ▾Hide ▴
Evidence considered
- REVEL: 0.386 (below typical 0.5 damaging threshold).
- BayesDel: 0.122929 (low probability of deleterious).
- SpliceAI max delta: 0.01 (no predicted splicing impact).
Sources
PP4 No patient phenotype data or family history specific to a disease with single genetic etiology is available for this variant. Details ▾Hide ▴
Still missing
- No phenotype data.
PP5 NM_014225.5:c.536C>G is absent from ClinVar with no classification from any submitter. PP5 requires a reputable source (≥3-star ClinVar expert panel) to have reported the variant as pathogenic. OncoKB classification ('Likely Oncogenic') is a somatic cancer database and does not qualify as a germline ClinVar expert panel classification. Details ▾Hide ▴
BA1 Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency does not exceed the BA1 threshold of 1% in any population database. Details ▾Hide ▴
BS1 Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency does not exceed the BS1 threshold of 0.3% in any population database. Details ▾Hide ▴
BS2 No observation of this variant in a homozygous or hemizygous state in healthy adults has been reported. Details ▾Hide ▴
Still missing
- No homozygote/hemizygote data.
BS3 Functional evidence from PMID:31142515 demonstrates a clear damaging loss-of-function effect: P179R disrupts PP2A holoenzyme assembly, reduces phosphatase activity, and promotes tumorigenesis. This directly contradicts a benign functional interpretation. Details ▾Hide ▴
Evidence considered
- Well-established functional studies show damaging
- not benign
- effect.
Sources
BS4 No segregation data in affected families is available to assess lack of segregation with disease. Details ▾Hide ▴
Still missing
- No segregation data.
BP1 PPP2R1A-related neurodevelopmental disorder (Houge-Janssens syndrome type 2, HJS2) is primarily caused by missense variants (PMID:37945024, PMID:40781915). Missense variants are a well-established disease mechanism for this gene; BP1, which applies when primarily truncating variants cause disease, does not apply. Details ▾Hide ▴
Evidence considered
- HJS2 neurodevelopmental disorder is caused by germline missense variants in PPP2R1A.
- Missense
- not truncating
- is the predominant pathogenic mechanism.
BP2 No phase data (in trans or in cis with a pathogenic variant) is available for this variant. Details ▾Hide ▴
Still missing
- No phase data.
BP4 Computational evidence is not consistently benign across tools. REVEL score of 0.386 is in a gray zone (below 0.5 but not definitively benign), BayesDel score of 0.123 is low, and SpliceAI max delta is 0.01. The mixed signal precludes a confident BP4 assignment. Details ▾Hide ▴
Evidence considered
- REVEL: 0.386 (gray zone
- below 0.5 but not clearly benign).
- BayesDel: 0.123 (low probability of deleterious).
- SpliceAI: 0.01 (no splicing impact).
Sources
BP5 No observation of this variant in a case with an alternate molecular basis for disease has been reported. Details ▾Hide ▴
Still missing
- No alternate-molecular-basis data.
BP6 NM_014225.5:c.536C>G is absent from ClinVar with no classification from any submitter. BP6 requires a reputable source (≥3-star ClinVar expert panel) to have reported the variant as benign. Details ▾Hide ▴
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions; this variant is a missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact; NM_014225.5:c.536C>G is a missense variant (p.Pro179Arg). Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 is not a standard criterion in the ACMG/AMP 2015 generic framework (Richards et al. 2015, PMID:25741868); no VCEP-specific PS5 definition exists for PPP2R1A. Details ▾Hide ▴
Sources
generic_acmg_combination_rules
Identifiers
- Gene
- PPP2R1A
- Transcript
- NM_014225.5
- Coding (HGVS c.)
- NM_014225.5:c.536C>G
- Protein (HGVS p.)
- NP_055040.2:p.(Pro179Arg)
- GRCh38
- chr19:52212718 C>G
- GRCh37
- chr19:52715971 C>G
- COSMIC
- COSV59042232
Gene diagram
Every interpreted variant in PPP2R1A, mapped onto the exon structure of NM_014225.5. Select a row to find it on the plot.
PPP2R1ANM_014225.5
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in PPP2R1A
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.386
- BayesDel
- 0.123
How the predictions were used
PP3 Computational predictors do not support a deleterious effect. REVEL score is 0.386 (below 0.5 threshold), BayesDel score is 0.123, and SpliceAI max delta is 0.01 (no splicing impact). Multiple lines of computational evidence do not support PP3. Details ▾Hide ▴
Evidence considered
- REVEL: 0.386 (below typical 0.5 damaging threshold).
- BayesDel: 0.122929 (low probability of deleterious).
- SpliceAI max delta: 0.01 (no predicted splicing impact).
Sources
BP4 Computational evidence is not consistently benign across tools. REVEL score of 0.386 is in a gray zone (below 0.5 but not definitively benign), BayesDel score of 0.123 is low, and SpliceAI max delta is 0.01. The mixed signal precludes a confident BP4 assignment. Details ▾Hide ▴
Evidence considered
- REVEL: 0.386 (gray zone
- below 0.5 but not clearly benign).
- BayesDel: 0.123 (low probability of deleterious).
- SpliceAI: 0.01 (no splicing impact).
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact; NM_014225.5:c.536C>G is a missense variant (p.Pro179Arg). Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.386. BayesDel score = 0.122929.
2 paper records listed. 1 cited in the classification.
Cited in the classification
-
PMID 31142515 ↗The Highly Recurrent PP2A Aα-Subunit Mutation P179R Alters Protein Structure and Impairs PP2A Enzyme Function to Promote Endometrial Tumorigenesis.P179R disrupts PP2A holoenzyme assembly by altering Aα-subunit conformation, leading to near-complete loss of catalytic C-subunit binding and proteasome-mediated C-subunit degradation. Restoration of wild-type Aα in P179R-mutant patient-derived endometrial carcinoma cells (UT42) suppresses tumorigenic features in xenograft models. Crystal structure of P179R-Aα determined at 3.4Å resolution (PDB 6EF4) reveals a closed conformation that excludes the catalytic subunit.→ PS3 → PM1 Names this variant
Source detail
the P179R mutation induced significant disruption of PP2A holoenzyme formation, presenting with a significant reduction in binding to members of each B-subunit family except the Striatins
Location Abstract; Results (Figures 1-5); Discussion; Methods (crystallography, co-IP, phosphatase assays, molecular dynamics); Supplementary Figures
Context Co-immunoprecipitation (UT89 serous endometrial carcinoma cells), X-ray crystallography (mouse PP2A Aα P179R, PDB 6EF4), molecular dynamics simulations, in vitro phosphatase activity assays, patient-derived cell lines (UT89, UT42), xenograft tumorigenesis assays
Other recorded publications
-
PMID 40604275 ↗PPP2R1A mutations portend improved survival after cancer immunotherapy.PPP2R1A P179R mutation in ovarian clear cell carcinoma was associated with significantly prolonged overall and progression-free survival after dual immune checkpoint blockade (nivolumab + ipilimumab). P179R overexpression in SKOV3 ovarian cancer cells increased sensitivity to CAR-T-cell-mediated killing.Names this variant
Quoted passage
cancer cells with the PPP2R1A mutant showed increased sensitivity to CAR-T-cell-mediated killing
Main text, Figure 4d and surrounding paragraphs; Extended Data Fig. 8
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_014225.5%3Ac.536C%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/19-52715971-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr19-52212718-C-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/19-52212718-C-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_014225.5%3Ac.536C…
- OncoKB ↗www.oncokb.org/gene/PPP2R1A/P179R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=128600288
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.386. BayesDel score = 0.122929.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV59042232, n = 92 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.