Variant classification summary

NM_000314.8:c.434T>G

PTEN · NP_000305.3:p.(Phe145Cys) · NM_000314.8

GRCh37: chr10:89692950 T>G · GRCh38: chr10:87933193 T>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.(Phe145Cys)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PTEN c.434T>G (p.Phe145Cys; p.F145C) variant has been observed once in somatic cancers in COSMIC and has not been reported in ClinVar.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PTEN PM2 threshold of 0.001% and supports PM2 at Supporting strength.

3

In the PTEN saturation mutagenesis phosphatase assay, p.Phe145Cys had a cumulative activity score of -0.669, which is above the PTEN PS3_Moderate cutoff of <= -1.11 and below the BS3 threshold of >0, so the current functional evidence does not independently meet PS3 or BS3.

4

Computational evidence supports a deleterious protein effect because the REVEL score is 0.861, above the PTEN PP3 threshold of >0.7, while SpliceAI predicts no significant splice effect with a maximum delta score of 0.01.

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 variant is a missense substitution, p.(Phe145Cys), and does not fall into the PTEN null-variant categories used for PVS1 such as nonsense, frameshift, or canonical +/-1,2 splice variants.	pvs1_gene_context pvs1_variant_assessment cspec vcep_pvs1_decisiontree_pten
PS1	Not assessed	No previously established pathogenic variant causing the same amino acid change was identified in the available evidence, so PS1 was not assessed.	clinvar cspec
PS2	Not assessed	No de novo data were identified for this variant, so PS2 was not assessed.	cspec
PS3	Not met	Functional testing from the PTEN saturation mutagenesis assay showed a cumulative phosphatase activity score of -0.669 for p.Phe145Cys, which is above the PTEN PS3_Moderate threshold of <= -1.11. No additional validated functional study showing splicing disruption or clearly damaging PTEN function was identified, so PS3 is not met.	vcep_mmc2 cspec
PS4	Not assessed	The available evidence does not provide germline proband counts, phenotype specificity scoring, or a case-control analysis showing enrichment in affected individuals, so PS4 was not assessed.	clinvar cspec
PM1	Not met	This missense variant affects residue 145, which is outside the PTEN catalytic motif residues defined for PM1 (90-94, 123-130, and 166-168). Available evidence also does not show a confirmed statistically significant hotspot for this residue, so PM1 is not met.	cspec hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PTEN PM2 threshold of <0.00001 (0.001%) and consistent with an ultra-rare allele in population databases.	gnomad_v2 gnomad_v4 cspec
PM3	N/A	PM3 is not applicable in the PTEN VCEP framework.	cspec
PM4	Not met	This variant is a missense substitution and does not cause an in-frame protein length change or stop-loss, so PM4 is not met.	cspec
PM5	Not assessed	No previously established pathogenic missense variant at residue Phe145 was identified in the available evidence, so PM5 was not assessed.	clinvar cspec
PM6	Not assessed	No assumed de novo observations were identified for this variant, so PM6 was not assessed.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 was not assessed.	cspec
PP2	Met	This variant is a missense change in PTEN, a gene for which the PTEN VCEP allows PP2 because benign missense variation is relatively low and missense change is an established disease mechanism.	cspec
PP3	Met	Computational evidence supports a deleterious effect for this missense variant because the REVEL score is 0.861, which is above the PTEN PP3 threshold of >0.7. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, so the in silico concern is for protein effect rather than splicing.	cspec spliceai
PP4	N/A	PP4 is not applicable in the PTEN VCEP framework because phenotype specificity is incorporated into PS4 specifications.	cspec
PP5	N/A	PP5 is not applicable in the PTEN VCEP framework.	cspec
BA1	Not met	This variant is absent from gnomAD v2.1 and v4.1 and therefore does not exceed the PTEN BA1 threshold of >0.00056 (0.056%).	gnomad_v2 gnomad_v4 cspec
BS1	Not met	This variant is absent from gnomAD v2.1 and v4.1 and therefore does not reach the PTEN BS1 thresholds of 0.0000043 to 0.000043 for Supporting or 0.000043 to 0.00056 for Strong evidence.	gnomad_v2 gnomad_v4 cspec
BS2	Not met	No observation of this variant in a healthy or PTEN-hamartoma-tumor-syndrome-unaffected homozygous individual was identified, so BS2 is not met.	gnomad_v2 gnomad_v4 cspec
BS3	Not met	Available functional evidence does not show normal PTEN function. In the Mighell assay, the cumulative phosphatase activity score for p.Phe145Cys is -0.669, which is below the PTEN BS3_Supporting threshold of >0, so BS3 is not met.	vcep_mmc2 cspec
BS4	Not assessed	No lack-of-segregation evidence was identified for this variant, so BS4 was not assessed.	cspec
BP1	N/A	BP1 is not applicable in the PTEN VCEP framework.	cspec
BP2	Not assessed	No phase data were identified showing this variant in trans with a pathogenic PTEN variant or in cis/unknown phase in at least three observations with different pathogenic PTEN variants, so BP2 was not assessed.	cspec
BP3	N/A	BP3 is not applicable in the PTEN VCEP framework.	cspec
BP4	Not met	Computational evidence does not support a benign protein effect for this missense variant because the REVEL score is 0.861, which is above the PTEN BP4 threshold of <0.5. Although SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, the missense prediction does not support BP4.	cspec spliceai
BP5	Not assessed	No evidence was identified that this variant was found in a case with a separate highly penetrant molecular diagnosis and a non-overlapping clinical history, so BP5 was not assessed.	cspec
BP6	N/A	BP6 is not applicable in the PTEN VCEP framework.	cspec
BP7	N/A	BP7 applies to synonymous or qualifying intronic variants and is not applicable to this missense variant.	cspec

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