Variant classification summary

NM_000314.8:c.638C>G

PTEN · NP_000305.3:p.(Pro213Arg) · NM_000314.8

GRCh37: chr10:89717613 C>G · GRCh38: chr10:87957856 C>G

Gene: PTEN Transcript: NM_000314.8

Final call

VUS

PM2 supporting PP2 supporting PP3 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Pro213Arg)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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.

3

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

4

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.

5

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.

6

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.

7

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.

8

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.

Final determination: No criteria-combination rule matched the adjudicated criteria in the Richards et.al., 2015 - Combining rules v3.2.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

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	This 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.	vcep_pvs1_decisiontree_pten pvs1_variant_assessment
PS1	Not met	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.	clinvar
PS2	Not assessed	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.
PS3	Not met	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.	vcep_mmc2 spliceai
PS4	Not assessed	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.
PS5	N/A	PS5 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.	cspec
PM1	Not met	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.	cspec
PM2	Met	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%).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	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.	clinvar pm5_candidates vcep_mmc2
PM6	Not assessed	No assumed or confirmed de novo observations were identified for this variant. No proband-level data with parental testing were available.
PP1	Not assessed	No co-segregation data are available for this variant. No family studies or meiosis counts were identified.
PP2	Met	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.	cspec
PP3	Met	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.	revel cspec
PP4	N/A	PP4 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.	cspec
PP5	N/A	PP5 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.	cspec
BA1	Not met	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%).	gnomad_v2 gnomad_v4
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	Not met	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).	gnomad_v2 gnomad_v4
BS3	Not met	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.	vcep_mmc2
BS4	Not assessed	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.
BP1	N/A	BP1 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.	cspec
BP2	Not met	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.
BP4	Not met	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.	revel spliceai cspec
BP5	Not met	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.
BP6	N/A	BP6 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.	cspec
BP7	N/A	BP7 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.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; this is a single-nucleotide substitution.
PM3	N/A	PM3 is not applicable to PTEN per VCEP v3.2.0 (recessive disorder criterion; PTEN-associated disorder is autosomal dominant).	cspec
PM4	N/A	PM4 applies to in-frame deletions/insertions and stop-loss variants causing protein length changes; this is a single-nucleotide missense substitution.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.