PTENc.638C>GUncertain significance

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Variant interpretation report

PTEN c.638C>G, p.(Pro213Arg)

NM_000314.8:c.638C>G NP_000305.3:p.(Pro213Arg) View identifiers

Classification

Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About PTEN

No gene-level summary was recorded for this case.

Key facts

Evidence used: 3 supporting (pathogenic)
Expert rules: ClinGen PTEN VCEP v3.2.0
Pipeline record: 19 Jun 2026

Evidence considered

View criteria

Applied evidence criteria

PM2 (supporting): This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). Allele frequency is below the PTEN VCEP PM2_Supporting threshold of <0.00001 (0.001%).
PP2 (supporting): PTEN has a low rate of benign missense variation and missense variants are a common mechanism of disease (PHTS, autosomal dominant). This is a missense variant (Pro213Arg). Per PTEN VCEP v3.2.0, PP2_Supporting applies to missense variants in PTEN.
PP3 (supporting): REVEL score is 0.868, exceeding the PTEN VCEP PP3 threshold of >0.7 for missense variants. This represents multiple lines of computational evidence (conservation, biochemical properties, and ensemble prediction) supporting a deleterious effect.

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 ClinGen PTEN VCEP v3.2.0. 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

PM2Supporting

PM2 · supporting

This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). Allele frequency is below the PTEN VCEP PM2_Supporting threshold of <0.00001 (0.001%).

PP2Supporting

PP2 · supporting

PTEN has a low rate of benign missense variation and missense variants are a common mechanism of disease (PHTS, autosomal dominant). This is a missense variant (Pro213Arg). Per PTEN VCEP v3.2.0, PP2_Supporting applies to missense variants in PTEN.

PP3Supporting

PP3 · supporting

REVEL score is 0.868, exceeding the PTEN VCEP PP3 threshold of >0.7 for missense variants. This represents multiple lines of computational evidence (conservation, biochemical properties, and ensemble prediction) supporting a deleterious effect.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework was evaluated deterministically with applied criteria: PM2 supporting, PP2 supporting, PP3 supporting; no rule matched the adjudicated criteria.

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.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.050 maximum delta

Recorded SpliceAI maximum delta score: 0.050. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

Functional evidence

Statement recorded

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.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV64295816, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under ClinGen PTEN VCEP v3.2.0, with the data and sources behind each one.

29 criteria with recorded statuses: 3 met · 11 not met · 5 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_000314.8:c.638C>G (p.Pro213Arg) is absent from all queried population databases (gnomAD v2.1, v4.1, Canada), meeting PM2_Supporting per PTEN VCEP v3.2.0.

PP2_Supporting is applied: this is a missense variant in PTEN, a gene with a low rate of benign missense variation where missense variants are a common disease mechanism per PTEN VCEP.

PP3_Supporting is applied: REVEL score 0.868 exceeds the PTEN VCEP threshold of >0.7 for missense variants, supporting a deleterious computational prediction.

PS3 was not met: the variant was not directly measured in the Mighell et al. 2018 phosphatase activity assay (Cum_score=NA), and the imputed score (−0.629) does not meet the PS3_Moderate threshold of ≤−1.11. No other variant-specific functional studies were identified.

PM1 was not met: codon 213 lies outside the VCEP-defined catalytic motifs (residues 90-94, 123-130, 166-168). No statistically significant hotspot was identified at this residue.

PVS1 is not applicable: the PTEN PVS1 decision tree is restricted to null variants (nonsense, frameshift, canonical splice site disruptions, exon deletions); missense substitutions are not within scope.

Remaining pathogenic criteria (PS1, PS2, PS4, PS5, PM5, PM6, PP1, PP4, PP5) and benign criteria (BA1, BS1-BS4, BP1-BP7) are either not met, not assessed due to absent data, or not applicable per PTEN VCEP v3.2.0.

Total evidence: PM2_Supporting + PP2_Supporting + PP3_Supporting. Per the PTEN VCEP classification rules (Richards et al. 2015 combination framework), this does not meet any pathogenic or likely pathogenic rule: Rule 4 requires one very strong criterion plus ≥2 supporting, which is not satisfied. The evidence is insufficient for classification beyond Variant of Uncertain Significance.

Met · 3

PM2 SupportingThis variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). Allele frequency is below the PTEN VCEP PM2_Supporting threshold of <0.00001 (0.001%). Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1
Absent from gnomAD v4.1
Absent from gnomAD-Canada v1.0

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

PP2 SupportingPTEN has a low rate of benign missense variation and missense variants are a common mechanism of disease (PHTS, autosomal dominant). This is a missense variant (Pro213Arg). Per PTEN VCEP v3.2.0, PP2_Supporting applies to missense variants in PTEN. Details ▾Hide ▴

Evidence considered

Missense variant (Pro213Arg) in PTEN
PTEN has low rate of benign missense variation per VCEP specification
Missense variants are a common mechanism of disease in PTEN

Sources

cspec ↗

PP3 SupportingREVEL score is 0.868, exceeding the PTEN VCEP PP3 threshold of >0.7 for missense variants. This represents multiple lines of computational evidence (conservation, biochemical properties, and ensemble prediction) supporting a deleterious effect. Details ▾Hide ▴

Evidence considered

REVEL score 0.868 (>0.7 per VCEP PP3 threshold for missense variants)

Sources

revelcspec ↗

Not met · 11 · evaluated, threshold not reached

PS1 PS1 requires the same amino acid change (Pro213Arg) to have been previously established as pathogenic regardless of nucleotide change. This variant is absent from ClinVar and no literature was identified reporting Pro213Arg as a known pathogenic variant. No evidence exists to support PS1. Details ▾Hide ▴

Evidence considered

Variant absent from ClinVar
no prior classification of P213R as pathogenic

Sources

clinvar ↗

PS3 PTEN VCEP PS3 criteria require either (a) RNA/mini-gene splicing impact (not applicable; SpliceAI max delta 0.05), (b) PS3_Moderate: phosphatase activity ≤ −1.11 per Mighell et al. 2018 (not met; this variant was not directly measured — Cum_score = NA, High_conf = NA; imputed score −0.629 does not meet the −1.11 threshold), or (c) PS3_Supporting: phosphatase activity <50% of wild-type or abnormal in vitro assay (imputed score alone is insufficient to establish this without direct measurement). No other variant-specific functional studies were identified. Details ▾Hide ▴

Evidence considered

Mighell et al. 2018 (PMID: 29706350) Table S2: P213R Cum_score=NA (not directly measured)
High_conf=NA
Imputed_Score=-0.629
Imputed score does not meet PS3_Moderate threshold of ≤ −1.11
SpliceAI max delta 0.05 — no splicing impact to assess via PS3 Strong

Still missing

No direct functional measurement for this variant in Mighell assay
No independent functional studies identified

Sources

vcep_mmc2spliceai ↗

PM1 PTEN VCEP defines PM1 as limited to residues in catalytic motifs: WPD loop (90-94), P-loop (123-130), and TI-loop (166-168) per NP_000305.3. Codon 213 lies outside these specified catalytic motif residues. The variant does not reside in a VCEP-defined mutational hotspot or critical functional domain for PM1 purposes. Details ▾Hide ▴

Evidence considered

Codon 213 is not within VCEP-defined catalytic motifs (90-94
123-130
166-168)
No statistically significant hotspot identified at this residue

Sources

cspec ↗

PM5 PM5 requires a different missense change at the same amino acid residue (codon 213) to have been previously classified as pathogenic or likely pathogenic. No such variant was identified: ClinVar contains no entries for this variant, and the pm5 candidate search returned zero comparator variants at codon 213. In the Mighell et al. 2018 dataset, P213A was directly measured but is not classified as pathogenic in ClinVar. Details ▾Hide ▴

Evidence considered

No pathogenic or likely pathogenic missense variant identified at codon 213 in ClinVar
PM5 candidate search returned zero qualifying comparator variants

Sources

clinvar ↗pm5_candidatesvcep_mmc2

BA1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency does not exceed the PTEN VCEP BA1 threshold of >0.00056 (0.056%). Details ▾Hide ▴

Evidence considered

Absent from gnomAD
AF not >0.00056

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 This variant is absent from gnomAD. Allele frequency does not fall within the PTEN VCEP BS1 range of 0.000043–0.00056 (0.0043%–0.056%) or the BS1_Supporting range of 0.0000043–0.000043. Details ▾Hide ▴

Evidence considered

Absent from gnomAD
AF not within BS1 or BS1_Supporting ranges

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS2 BS2 requires observation in the homozygous state in a healthy or PHTS-unaffected individual. This variant is absent from gnomAD (zero alleles observed, zero homozygotes). Details ▾Hide ▴

Evidence considered

Zero homozygotes observed in gnomAD

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS3 BS3 per PTEN VCEP requires functional studies showing no damaging effect. BS3_Supporting requires phosphatase activity >0 per Mighell et al. 2018. The imputed score for P213R is −0.629 (negative, indicating reduced activity, not benign). No direct measurements or other functional studies showing no damaging effect were identified. Details ▾Hide ▴

Evidence considered

Mighell et al. 2018: P213R Imputed_Score = −0.629 (not >0
does not support BS3_Supporting)
No direct functional measurement available (Cum_score=NA)

Still missing

No direct functional measurement for this variant

Sources

vcep_mmc2

BP2 BP2 requires observation in trans with a pathogenic/likely pathogenic PTEN variant, or at least three observations in cis/phase unknown with different pathogenic/likely pathogenic PTEN variants. No such observations are available for this variant. Details ▾Hide ▴

Evidence considered

No evidence of in trans or in cis observation with pathogenic PTEN variants

BP4 PTEN VCEP BP4_Supporting for missense variants requires REVEL score <0.5. REVEL score for this variant is 0.868, which does not meet this threshold. SpliceAI max delta 0.05 indicates no splicing impact, but BP4 for missense is evaluated by REVEL per VCEP specification. Details ▾Hide ▴

Evidence considered

REVEL score 0.868 (not <0.5 per VCEP BP4 threshold for missense)
SpliceAI max delta 0.05 — no splicing impact

Sources

revelspliceai ↗cspec ↗

BP5 BP5 requires the variant to be found in a case with an alternate molecular basis for disease (at least two such cases per PTEN VCEP). No such cases were identified for this variant. Details ▾Hide ▴

Evidence considered

No cases with alternate molecular basis identified

Not assessed · 5 · no assessment recorded

PS2 No de novo observation data were identified for this variant. No proband-level clinical data, parental testing results, or published de novo reports mention NM_000314.8:c.638C>G. Details ▾Hide ▴

Still missing

No de novo reports or parental testing data available

PS4 No proband count or phenotype specificity data are available for this variant. PS4 per PTEN VCEP requires proband specificity scores or case-control data; none were identified. Details ▾Hide ▴

Still missing

No proband or case-control data available

PM6 No assumed or confirmed de novo observations were identified for this variant. No proband-level data with parental testing were available. Details ▾Hide ▴

Still missing

No de novo reports available

PP1 No co-segregation data are available for this variant. No family studies or meiosis counts were identified. Details ▾Hide ▴

Still missing

No segregation or family data available

BS4 No segregation data are available to assess lack of segregation in affected family members. BS4 requires lack of segregation in one (supporting) or two or more (strong) families. Details ▾Hide ▴

Still missing

No family segregation data available

Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AThis is a missense variant (c.638C>G, p.Pro213Arg). The PTEN PVS1 decision tree per the ClinGen PTEN Expert Panel v3.2.0 applies only to null variants (nonsense, frameshift, canonical ±1,2 splice site disruptions, and single/multi-exon deletions). Missense substitutions are not within the scope of PVS1 per this VCEP framework. Details ▾Hide ▴

Evidence considered

Variant class is substitution (missense
Pro213Arg)
PTEN PVS1 decision tree restricted to null variants per VCEP v3.2.0

Sources

vcep_pvs1_decisiontree_ptenpvs1_variant_assessment

PM3 VCEPPM3 is not applicable to PTEN per VCEP v3.2.0 (recessive disorder criterion; PTEN-associated disorder is autosomal dominant). Details ▾Hide ▴

Sources

cspec ↗

PM4 N/APM4 applies to in-frame deletions/insertions and stop-loss variants causing protein length changes; this is a single-nucleotide missense substitution. Details ▾Hide ▴

No further detail was recorded.

PP4 VCEPPP4 is marked Not Applicable by the ClinGen PTEN Expert Panel v3.2.0. Phenotype specificity has been incorporated into the rule specifications for PS4 per VCEP. Details ▾Hide ▴

Evidence considered

VCEP PTEN v3.2.0: PP4 not applicable
phenotype specificity incorporated into PS4

Sources

cspec ↗

PP5 VCEPPP5 is marked Not Applicable for this VCEP by the ClinGen PTEN Expert Panel v3.2.0 per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴

Evidence considered

PTEN VCEP v3.2.0: PP5 not for use per ClinGen SVI VCEP Review Committee

Sources

cspec ↗

BP1 VCEPBP1 is marked Not Applicable by the ClinGen PTEN Expert Panel v3.2.0. This criterion (missense variant in gene where primarily truncating variants cause disease) is not applicable to PTEN. Details ▾Hide ▴

Evidence considered

PTEN VCEP v3.2.0: BP1 not applicable to PTEN

Sources

cspec ↗

BP3 VCEPBP3 applies to in-frame deletions/insertions in repetitive regions; this is a single-nucleotide substitution. Details ▾Hide ▴

No further detail was recorded.

BP6 VCEPBP6 is marked Not Applicable for this VCEP by the ClinGen PTEN Expert Panel v3.2.0 per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴

Evidence considered

PTEN VCEP v3.2.0: BP6 not for use per ClinGen SVI VCEP Review Committee

Sources

cspec ↗

BP7 N/ABP7 applies to synonymous (silent) or intronic variants at or beyond +7/−21 with no predicted splicing impact. NM_000314.8:c.638C>G is a missense variant (Pro213Arg), not synonymous or intronic. Details ▾Hide ▴

Evidence considered

Variant is missense (Pro213Arg)
not synonymous or intronic

PS5 N/APS5 is not a criterion in the ACMG/AMP 2015 framework. The ClinGen PTEN VCEP v3.2.0 does not define a PS5 criterion. PP5 (reputable source reports variant as pathogenic) is marked Not Applicable by the PTEN VCEP. Details ▾Hide ▴

Evidence considered

No PS5 criterion exists in ACMG/AMP or PTEN VCEP frameworks

Sources

cspec ↗

Identifiers

Gene: PTEN
Transcript: NM_000314.8
Coding (HGVS c.): NM_000314.8:c.638C>G
Protein (HGVS p.): NP_000305.3:p.(Pro213Arg)
GRCh38: chr10:87957856 C>G
GRCh37: chr10:89717613 C>G
COSMIC: COSV64295816

Gene diagram

Every interpreted variant in PTEN, mapped onto the exon structure of NM_000314.8. Select a row to find it on the plot.

PTENNM_000314.8

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 PTEN — 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

SpliceAI acceptor lossat +51 bp

0.050

SpliceAI acceptor gainat -3 bp

0.000

SpliceAI donor lossat -24 bp

0.000

SpliceAI donor gainat +25 bp

0.000

Pangolin splice lossmagnitude shown

-0.020

Pangolin splice gain

0.010

Other predictors

REVEL: 0.868
BayesDel: 0.342

How the predictions were used

Evidence considered

REVEL score 0.868 (>0.7 per VCEP PP3 threshold for missense variants)

Sources

revelcspec ↗

Evidence considered

REVEL score 0.868 (not <0.5 per VCEP BP4 threshold for missense)
SpliceAI max delta 0.05 — no splicing impact

Sources

revelspliceai ↗cspec ↗

Evidence considered

Variant is missense (Pro213Arg)
not synonymous or intronic

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.868. BayesDel score = 0.341906.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

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 0.050 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 ↗

ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

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 = 0.05). REVEL score = 0.868. BayesDel score = 0.341906.

Functional

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV64295816, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.