Variant classification summary

NM_000314.8:c.388C>G

PTEN · NP_000305.3:p.(Arg130Gly) · NM_000314.8

GRCh37: chr10:89692904 C>G · GRCh38: chr10:87933147 C>G

Gene: PTEN Transcript: NM_000314.8

Final call

Likely Pathogenic

PS3 moderate PM1 moderate PM2 supporting PM5 moderate PP2 supporting PP3 supporting PP5 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Arg130Gly)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000314.8:c.388C>G (p.Arg130Gly) in PTEN is classified as Likely Pathogenic per the ClinGen PTEN Expert Panel Specifications Version 3.2.0, based on three moderate and three supporting criteria.

2

The variant is located in the PTEN catalytic P-loop (Arg130, residues 123–130), a critical functional domain defined by the VCEP as a mutational hotspot and catalytic motif (PM1).

3

PTEN phosphatase activity assay via saturation mutagenesis (Mighell et al. 2018) yields Cum_score = -2.14 (High_conf = True), meeting the VCEP PS3_Moderate threshold of ≤ -1.11. Functional studies demonstrate that R130G produces fully inactive PTEN protein with complete loss of PIP3 phosphatase activity in yeast (PMID:21828076) and abrogated tumor suppressive function in glioma cells (PMID:11948419).

4

Other missense changes at Arg130 (R130Q, R130L, R130P) are established as pathogenic/likely pathogenic in ClinVar in association with Cowden syndrome/PHTS, and the BLOSUM62 score of R130G (-2) is less than or equal to these comparators, satisfying PM5.

5

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the VCEP PM2_Supporting threshold of <0.001% allele frequency.

6

PP2 applies as PTEN has a low rate of benign missense variation and missense variants are a common disease mechanism. PP3 applies with a REVEL score of 0.962 (>0.7 threshold).

7

The variant has been reported in ClinVar as Pathogenic by the Clingen PTEN Variant Curation Expert Panel (expert panel review) and as Pathogenic by four clinical laboratories. It is also reported in COSMIC (259 somatic observations) and classified as Oncogenic (loss-of-function) by OncoKB.

8

Applying the PTEN VCEP classification combining rules: ≥3 moderate criteria (PS3_Moderate, PM1, PM5) satisfies Rule13 for Likely Pathogenic. The ClinVar expert panel classification of Pathogenic suggests additional proband-level evidence (PS4) may be available to elevate this to Pathogenic.

Final determination: Rule13 in the Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Likely Pathogenic.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Missense variant (c.388C>G, p.Arg130Gly). The PTEN VCEP PVS1 decision tree applies only to null variants (nonsense, frameshift, canonical ±1,2 splice site disruptions, and single/multi-exon deletions). Missense variants are not eligible for PVS1 under this framework.
PS1	Not met	No evidence of a different nucleotide change at NM_000314.8:c.388 that produces the same p.Arg130Gly amino acid substitution. The codon CGA can only yield Gly via a C>G transversion at the first position; no alternative nucleotide change creates R130G at this residue.
PS2	Not assessed	No de novo observation data (maternity and paternity confirmed) available in the case evidence for NM_000314.8:c.388C>G. ClinVar submissions and reviewed literature do not report a confirmed de novo occurrence.
PS3	Met	PTEN phosphatase activity assay (Mighell et al. 2018, saturation mutagenesis) yields a cumulative fitness score (Cum_score) of -2.14 for R130G (High_conf=True), meeting the VCEP threshold of ≤ -1.11 for PS3_Moderate. Additionally, R130G was shown to produce fully inactive PTEN protein in a yeast-based in vivo PIP3 phosphatase assay (PMID:21828076) and abrogated tumor suppressive activity including colony formation and growth inhibition in glioma cells (PMID:11948419).	vcep_mmc2 PMID:21828076 PMID:11948419
PS4	Not assessed	Proband specificity scores and case-control data required for PS4 strength determination per the PTEN VCEP are not available in the evidence provided. The variant is classified as Pathogenic in ClinVar (reviewed by expert panel, multiple clinical laboratory submissions), suggesting significant proband-level data exist, but the raw counts needed to calculate specificity scores were not located.	clinvar
PS5	N/A	PS5 is not defined in the ClinGen PTEN Expert Panel Specifications Version 3.2.0. The criterion is not part of the PTEN VCEP framework.
PM1	Met	Arg130 is located within the PTEN catalytic P-loop (residues 123–130, NP_000305.3), which is a critical and well-established functional domain defined by the VCEP as a mutational hotspot and catalytic motif. The P-loop contains the essential catalytic Cys124 and Arg130 residues at the active site. Residue 130 is a statistically significant hotspot.	cspec
PM2	Met	NM_000314.8:c.388C>G is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes + genomes), and gnomAD-Canada v1.0. Allele frequency is <0.00001 (0.001%) across all populations, meeting the PTEN VCEP PM2_Supporting threshold.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Met	R130G is a missense change at Arg130, where other missense changes (R130Q, R130L, R130P) are established as pathogenic/likely pathogenic in ClinVar and associated with Cowden syndrome/PHTS in the literature. The interrogated variant R130G has a BLOSUM62 score of -2 (Arg→Gly), which is less than or equal to known pathogenic variants at this residue (R130Q: +1, R130L: -2, R130P: -2), satisfying the VCEP PM5 BLOSUM62 requirement.	clinvar vcep_mmc2
PM6	Not assessed	No de novo occurrence data (assumed or confirmed) available for this variant. ClinVar submissions and reviewed literature do not report de novo observations.
PP1	Not assessed	No co-segregation data available in the evidence provided. Family-level meiotic data would be needed to assess co-segregation with disease.
PP2	Met	PTEN is a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease (PHTS, Cowden syndrome). The variant is a missense change, satisfying the VCEP PP2 rule.	cspec
PP3	Met	REVEL score of 0.962 exceeds the VCEP threshold of >0.7 for PP3 supporting evidence. Multiple lines of computational evidence support a deleterious effect: REVEL 0.962 (highly deleterious), BayesDel 0.581 (deleterious). SpliceAI max delta 0.02 indicates no splicing impact, consistent with a missense mechanism of pathogenicity rather than splicing.	revel bayesdel spliceai
PP4	N/A	PP4 is explicitly marked as Not Applicable by the ClinGen PTEN Expert Panel Specifications Version 3.2.0. Phenotype specificity has been incorporated into the PS4 rule specifications.	cspec
PP5	Met	Expert panel Clingen PTEN Variant Curation Expert Panel, Clingen classified as Pathogenic.	cspec clinvar
BA1	Not met	Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Does not meet the PTEN VCEP BA1 threshold of allele frequency >0.00056 (0.056%).	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Variant is absent from all gnomAD populations. Does not meet the PTEN VCEP BS1 threshold (AF ≥0.0000043 for supporting or ≥0.000043 for strong).	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No homozygous observations in gnomAD or other population databases. The variant is entirely absent from population cohorts, providing no evidence of homozygous or healthy adult occurrence.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not met	PTEN phosphatase activity assay (Mighell et al. 2018) shows Cum_score = -2.14 for R130G, which is ≤0 and indicates damaging effect. BS3_Supporting requires phosphatase activity >0. The variant does not meet BS3 criteria. BS3_Strong applies only to splicing assays (not relevant for this missense variant).	vcep_mmc2
BS4	Not assessed	No segregation data available to assess lack of segregation in affected family members.
BP1	N/A	BP1 is explicitly marked as Not Applicable by the ClinGen PTEN Expert Panel Specifications Version 3.2.0.	cspec
BP2	Not assessed	No data on observations in trans or cis with pathogenic PTEN variants available.
BP3	N/A	Skipped per instruction: in-frame indels not relevant to this substitution variant.
BP4	Not met	REVEL score of 0.962 exceeds the VCEP BP4 threshold of <0.5 for benign computational evidence. Multiple in silico predictions support a deleterious effect, not a benign one.	revel bayesdel
BP5	Not assessed	No evidence of an alternate molecular basis for disease in a proband carrying this variant. Individual case-level data would be required.
BP6	N/A	BP6 is explicitly marked as Not Applicable by the ClinGen PTEN Expert Panel Specifications Version 3.2.0.	cspec
BP7	N/A	BP7 applies to synonymous (silent) or intronic variants for which splicing prediction algorithms predict no impact. NM_000314.8:c.388C>G is a missense variant producing p.Arg130Gly and does not qualify.

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