Variant classification summary

NM_000314.8:c.106G>C

PTEN · NP_000305.3:p.(Gly36Arg) · NM_000314.8

GRCh37: chr10:89653808 G>C · GRCh38: chr10:87894051 G>C

Gene: PTEN Transcript: NM_000314.8

Final call

Pathogenic

PS1 strong PS3 moderate PM2 supporting PP2 supporting PP3 supporting PP5 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Gly36Arg)

gnomAD AF

ClinVar

Likely pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000314.8:c.106G>C (p.Gly36Arg) is a missense variant in PTEN exon 2. It is absent from all large population databases (gnomAD v2.1, v4.1, gnomAD-Canada).

2

The same amino acid change (p.Gly36Arg) from a different nucleotide substitution (c.106G>A) is classified as Likely Pathogenic by the ClinGen PTEN Variant Curation Expert Panel in ClinVar (VCV000189400, 3-star review).

3

Saturation mutagenesis functional data from Mighell et al. 2018 (PMID:29706350) demonstrate a severe damaging effect: G36R cumulative fitness score is -2.69 (threshold for PS3_Moderate is <= -1.11).

4

Additional functional studies corroborate the damaging effect: PMID:10772390 demonstrated 90% loss of phosphatase activity for G36R, and PMID:21828076 confirmed loss of function in a yeast in vivo assay.

5

In silico predictions uniformly support pathogenicity: REVEL score 0.995 and BayesDel score 0.617.

6

Applying the ClinGen PTEN VCEP v3.2.0 combination rules: PS1 (strong) is met (same amino acid change as established pathogenic c.106G>A); PS3_Moderate is met (Mighell et al. Cum_score -2.69 <= -1.11); and multiple supporting criteria are met (PM2_Supporting, PP2, PP3, PP5). Per VCEP Rule 11, one strong criterion (PS1) plus one moderate criterion (PS3_Moderate) is sufficient for a Likely Pathogenic classification.

Final determination: Rule8 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 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	PVS1 is not applicable to missense variants. The PTEN VCEP PVS1 decision tree (NM_000314.8) is limited to null variants: nonsense, frameshift, canonical GT-AG splice site disruptions, and single/multi-exon deletions with positional assessment relative to p.D375 (c.1121). NM_000314.8:c.106G>C is a missense substitution (p.Gly36Arg) and does not fall into any PVS1-eligible null variant bucket.	vcep_pvs1_decisiontree_pten pvs1_variant_assessment
PS1	Met	NM_000314.8:c.106G>C encodes p.Gly36Arg (G36R). A different nucleotide substitution at the same codon, NM_000314.8:c.106G>A, also encoding p.Gly36Arg, is established as pathogenic: ClinVar 3-star expert panel classifies it as Likely Pathogenic (VCV000189400), and it has been reported in a Cowden syndrome proband with bilateral breast cancer (PMID:10772390) with demonstrated 90% loss of phosphatase activity. The VCEP PS1 rule is satisfied: same amino acid change as a previously established pathogenic variant regardless of nucleotide change.	clinvar PMID:10772390
PS2	Not met	No de novo observation has been identified for this variant. Parental testing data confirming de novo occurrence of NM_000314.8:c.106G>C in a patient with PTEN hamartoma tumor syndrome and no family history is absent from all reviewed sources.
PS3	Met	The PTEN G36R variant has a cumulative fitness score (Cum_score) of -2.69 in the Mighell et al. 2018 (PMID:29706350) saturation mutagenesis functional assay (mmc2.xlsx Table S2), meeting the VCEP PS3_Moderate threshold of Cum_score <= -1.11. High_conf = True and the variant Pass SE Filter. This is a massively parallel phosphatase activity assay directly testing all possible PTEN missense variants. The damaging functional effect is corroborated by PMID:10772390 (90% loss of phosphatase activity for G36R from c.106G>A) and PMID:21828076 (G36R tested among PHTS-associated mutations in yeast in vivo model, showing loss of function).	vcep_mmc2 PMID:10772390 PMID:21828076
PS4	Not met	Only a single proband with this variant has been identified in the reviewed literature (PMID:10772390 reports a Cowden syndrome patient with c.106G>A, same amino acid change). The VCEP PTEN PS4 rule requires a specificity score of at least 1-1.5 for supporting evidence, >=2 for moderate, >=4 for strong, and >=16 for very strong. A single proband does not meet any VCEP PS4 threshold.	PMID:10772390
PS5	N/A	Not a standard ACMG/AMP criterion in the PTEN VCEP framework. The same-amino-acid-change scenario for this variant is fully adjudicated under PS1.
PM1	Not met	G36 is located in the N-terminal region of PTEN (position 36 of NP_000305.3). The PTEN VCEP defines PM1 specifically for residues in the catalytic motifs: 90-94 (WPD-loop), 123-130 (P-loop), and 166-168 (TI-loop). G36 is outside these defined critical functional domains. While cancerhotspots.org identifies this as a statistically significant hotspot in somatic contexts, the VCEP has restricted PM1 application to the specified catalytic motif residues for germline interpretation.	cspec
PM2	Met	NM_000314.8:c.106G>C is absent from all large population databases: gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (HostSeq genomes). The VCEP PTEN PM2 rule applies at supporting strength when a variant is absent or present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No different missense variant at residue G36 has been independently classified as Pathogenic or Likely Pathogenic in ClinVar with expert panel review to satisfy the VCEP PM5 rule. Per the VCEP PTEN PM5 rule, a missense change at an amino acid residue where a different missense change has been determined to be P/LP, with the interrogated variant having a BLOSUM62 score equal to or less than the known variant, is required.	pm5_candidates
PM6	Not met	No de novo observation has been identified for NM_000314.8:c.106G>C. No assumed or confirmed de novo occurrence in a patient with PTEN hamartoma tumor syndrome and no family history is documented in any reviewed source.
PP1	Not met	No co-segregation data are available for this variant. The VCEP PTEN PP1 rule requires at least 3-4 meioses for supporting level; no family studies with segregation analysis have been identified.
PP2	Met	PTEN has a low rate of benign missense variation and missense variants are a common mechanism of disease in PTEN hamartoma tumor syndrome. NM_000314.8:c.106G>C is a missense variant in a gene meeting these criteria, satisfying the VCEP PTEN PP2 rule at supporting strength.	cspec
PP3	Met	Multiple lines of in silico evidence support a deleterious effect. The REVEL score is 0.995, which exceeds the VCEP PTEN PP3 threshold of >0.7 for missense variants. The BayesDel score is 0.617, providing additional orthogonal support for a damaging prediction.	revel bayesdel
PP4	N/A	The PTEN VCEP specifies PP4 as 'Not Applicable' because phenotype specificity has been incorporated into the PS4 rule specifications.	cspec
PP5	Met	Expert panel Clingen PTEN Variant Curation Expert Panel, Clingen classified as Likely pathogenic.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The VCEP PTEN BA1 threshold of filtering allele frequency >0.00056 (0.056%) is not met.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD. The VCEP PTEN BS1 thresholds are not met: the allele frequency is 0, which is below the BS1_Strong threshold of >=0.000043 (0.0043%) and the BS1_Supporting threshold of >=0.0000043 (0.00043%).	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous observations of this variant have been identified in healthy or PHTS-unaffected individuals. The VCEP PTEN BS2 rule requires observation in the homozygous state in a healthy or PHTS-unaffected individual.	gnomad_v2 gnomad_v4
BS3	Not met	The functional data demonstrate a damaging effect, not a benign effect. G36R has a cumulative fitness score of -2.69 in the Mighell et al. 2018 saturation mutagenesis assay (mmc2.xlsx), which meets PS3_Moderate criteria rather than BS3. The VCEP PTEN BS3_Supporting threshold requires phosphatase activity >0, which is not met.	vcep_mmc2
BS4	Not met	No segregation data are available to evaluate lack of segregation. No family studies showing non-segregation of this variant with disease have been identified.
BP1	N/A	The PTEN VCEP specifies BP1 as 'Not Applicable.'	cspec
BP2	Not met	No observations of this variant in trans with a pathogenic or likely pathogenic PTEN variant, nor three or more observations in cis or unknown phase with different P/LP PTEN variants, have been identified.
BP4	Not met	Computational evidence does not suggest a benign impact. The REVEL score is 0.995 (well above the VCEP BP4 threshold of <0.5 for missense variants). The SpliceAI maximum delta score is 0.27, which is above the 0.2 threshold for benign splicing prediction. BP4 is not met.	revel spliceai
BP5	Not met	No case has been identified where this variant was found in a patient with an alternate molecular basis for disease. The VCEP PTEN BP5 rule requires at least two such cases with a highly penetrant alternate gene/disorder and no phenotypic overlap with PTEN.
BP6	N/A	The PTEN VCEP designates BP6 as 'Not Applicable for this VCEP' per ClinGen SVI VCEP Review Committee recommendation. Additionally, the ClinVar expert panel classification for this variant is Likely Pathogenic (not benign), so BP6 evidence of a benign classification from a reputable source is not available even if the criterion were applied.	cspec clinvar
BP7	Not met	NM_000314.8:c.106G>C is a missense variant (p.Gly36Arg), not a synonymous or intronic variant. The VCEP PTEN BP7 rule applies only to synonymous or intronic variants at or beyond +7/-21 for which splicing prediction algorithms predict no impact to the splice consensus sequence.
BP3	N/A	Skipped per workflow directive.
PM3	N/A	Skipped per workflow directive.
PM4	N/A	Skipped per workflow directive.

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