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

VUS

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, a tumor suppressor gene where loss-of-function is an established mechanism for PTEN hamartoma tumor syndrome (autosomal dominant).

2

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting PM2_Supporting under PTEN VCEP criteria (allele frequency < 0.001%).

3

Functional data from Mighell et al. 2018 saturation mutagenesis (PMID:29706350, VCEP mmc2.xlsx Table S2) show G36R with a cumulative fitness score of -2.69 (High_conf=True), meeting the VCEP PS3_Moderate threshold of ≤ -1.11.

4

An independent functional study (PMID:10772390) reported that the same amino acid change p.Gly36Arg (produced by c.106G>A) resulted in approximately 90% loss of PTEN phosphatase activity in a recombinant assay.

5

REVEL score is 0.995 (> 0.7 VCEP threshold), meeting PP3 at Supporting strength. PP2 is met at Supporting as PTEN has a low rate of benign missense variation and missense variants are a common disease mechanism.

6

ClinVar VariationID 189400 (encompassing c.106G>C and c.106G>A, both p.Gly36Arg) is classified as Likely pathogenic by the ClinGen PTEN VCEP (reviewed by expert panel), with one clinical laboratory submitting as Pathogenic and one as Uncertain significance.

7

Combined evidence: 1 moderate pathogenic criterion (PS3_Moderate) and 3 supporting pathogenic criteria (PM2_Supporting, PP2, PP3). Under the ClinGen PTEN VCEP v3.2.0 classification framework, this combination does not meet any pathogenic or likely pathogenic rule. The variant is classified as Uncertain Significance (VUS).

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	NM_000314.8:c.106G>C is a missense variant producing p.(Gly36Arg). The PTEN VCEP PVS1 decision tree applies only to null variants (nonsense, frameshift, canonical splice site disruptions, CNVs). This missense substitution does not fall into any PVS1 bucket.	pvs1_gene_context pvs1_variant_assessment vcep_pvs1_decisiontree_pten
PS1	Not met	The c.106G>A variant producing the same p.(Gly36Arg) amino acid change has been reported in a Cowden syndrome family (PMID:10772390) and is encompassed within ClinVar VariationID 189400 with an expert panel classification of Likely pathogenic. However, the VCEP PS1 rule requires a previously established pathogenic variant, and the ClinGen PTEN VCEP classification for this variation ID is Likely pathogenic, not Pathogenic. PS1 is not met.	PMID:10772390 clinvar
PS2	Not met	No de novo observation data (confirmed or assumed) for this variant was identified in any publication reviewed.
PS3	Met	The PTEN VCEP specifies PS3_Moderate for phosphatase activity ≤ -1.11 per Mighell et al. 2018 (PMID:29706350). In the VCEP-curated saturation mutagenesis dataset (mmc2.xlsx, Table S2), the G36R variant has a cumulative fitness score (Cum_score) of -2.69 (High_conf=True, Pass SE Filter), meeting the ≤ -1.11 threshold. This demonstrates a damaging effect on PTEN phosphatase activity in a systematic functional assay.	vcep_mmc2
PS4	Not met	The PTEN VCEP requires proband specificity scores (≥1 for Supporting, ≥2 for Moderate, ≥4 for Strong). No proband count or specificity score data are available for this variant in the case materials. A single Cowden syndrome proband with c.106G>A (same amino acid change) is reported in PMID:10772390, but this is insufficient for any PS4 strength level under the VCEP framework.	PMID:10772390
PS5	Not assessed	PS5 (variant found in a case with an alternate molecular basis but not in controls) is not part of the standard ACMG/AMP criteria set. This criterion is not defined in the PTEN VCEP specifications. No primary data available in case materials.
PM1	Not met	The PTEN VCEP defines PM1 as a variant located in catalytic motifs: residues 90-94, 123-130, or 166-168 (NP_000305.3). The p.Gly36Arg change is at residue 36, which lies outside these defined catalytic motifs. Although the residue is in a statistically significant hotspot (cancerhotspots.org), the VCEP specification restricts PM1 to the three catalytic motif regions.	cspec
PM2	Met	The PTEN VCEP specifies PM2 at Supporting strength for variants absent from gnomAD at allele frequency < 0.001% (0.00001). The variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not assessed	PM5 requires a different missense change at the same amino acid residue (Gly36) that is classified as pathogenic or likely pathogenic, with a BLOSUM62 score comparison. The automated PM5 pipeline did not generate comparator candidates for this case (pm5_candidates.json: found=false, reason='variant class is not missense-like'). Manual ClinVar review of other Gly36 missense variants (e.g., G36V, G36E, G36D) is needed to adjudicate PM5.	pm5_candidates
PM6	Not met	No de novo observation data (confirmed or assumed) for this variant was identified in any publication or ClinVar submission reviewed.
PP1	Not met	The PTEN VCEP requires 3-4 meioses for PP1 at Supporting level. No segregation data are available for this variant. The single proband reported in PMID:10772390 does not provide multi-generational segregation evidence.
PP2	Met	The PTEN VCEP specifies PP2 at Supporting strength for missense variants in a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease. PTEN is a well-established tumor suppressor gene where missense variants are a known disease mechanism in PTEN hamartoma tumor syndrome (PHTS). PTEN shows strong missense constraint in population databases.	cspec
PP3	Met	The PTEN VCEP specifies PP3 at Supporting strength for missense variants with REVEL score > 0.7. The REVEL score for NM_000314.8:c.106G>C (p.Gly36Arg) is 0.995, well above the 0.7 threshold. The BayesDel score (0.617) provides additional computational support. SpliceAI max delta is 0.27, which does not strongly predict splicing impact but is consistent with a possible effect.	revel bayesdel spliceai
PP4	N/A	The PTEN VCEP specifies PP4 as Not Applicable. Phenotype specificity has been incorporated into the rule specifications for PS4 Use 2.	cspec
PP5	Met	Expert panel Clingen PTEN Variant Curation Expert Panel, Clingen classified as Likely pathogenic.	cspec clinvar
BA1	Not met	The PTEN VCEP specifies BA1 for gnomAD filtering allele frequency > 0.056% (0.00056). The variant is absent from gnomAD v2.1 and v4.1. BA1 is not met.	gnomad_v2 gnomad_v4
BS1	Not met	The PTEN VCEP specifies BS1 for gnomAD filtering allele frequency ≥ 0.00043% (Supporting) to ≥ 0.0043% (Strong). The variant is absent from all gnomAD datasets. BS1 is not met.	gnomad_v2 gnomad_v4
BS2	Not met	The PTEN VCEP requires observation in the homozygous state in a healthy or PHTS-unaffected individual. No homozygous observations for this variant are recorded in gnomAD or any publication reviewed.	gnomad_v2 gnomad_v4
BS3	Not met	The PTEN VCEP specifies BS3_Supporting for phosphatase activity > 0 per Mighell et al. 2018 (PMID:29706350). The G36R variant has a Cum_score of -2.69, which is strongly damaging (≤ -1.11 threshold meets PS3_Moderate instead). BS3 is not met because the functional data demonstrate a damaging, not benign, effect.	vcep_mmc2
BS4	Not met	The PTEN VCEP requires lack of segregation in affected members of one family (Supporting) or two or more families (Strong). No segregation data (for or against segregation) are available for this variant.
BP1	N/A	The PTEN VCEP specifies BP1 as Not Applicable.	cspec
BP2	Not met	The PTEN VCEP requires observation in trans with a pathogenic or likely pathogenic PTEN variant, or at least three observations in cis/phase unknown with different P/LP variants. No such data are available for this variant.
BP4	Not met	The PTEN VCEP specifies BP4 for missense variants with REVEL score < 0.5 (Supporting). The REVEL score for this variant is 0.995, which is strongly predictive of a deleterious effect and directly opposes a BP4 determination. Additionally, multiple computational tools (BayesDel 0.617, SpliceAI max delta 0.27) support a damaging effect.	revel bayesdel spliceai
BP5	Not met	The PTEN VCEP requires the variant to be found in a case with an alternate molecular basis for disease, where the other gene/disorder is highly penetrant and the patient's history shows no overlap with PTEN. At least two such cases are required. No such data are available.
BP6	N/A	The PTEN VCEP specifies BP6 as Not Applicable for this VCEP, consistent with ClinGen SVI VCEP Review Committee recommendations.	cspec
BP7	Not met	BP7 applies to synonymous (silent) or intronic variants at or beyond +7/-21 for which splicing prediction algorithms predict no impact. NM_000314.8:c.106G>C is a missense variant in exon 2; BP7 is not applicable to missense changes.
BP3	N/A	In-frame deletion/insertion criterion; not applicable to missense substitution variant.
PM3	N/A	Recessive/trans criterion; PTEN is a dominant disorder gene.
PM4	N/A	Protein-length change criterion for in-frame indels/stop-loss; not applicable to missense substitution.

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