Variant classification summary

NM_000314.8:c.367C>G

PTEN · NP_000305.3:p.(His123Asp) · NM_000314.8

GRCh37: chr10:89692883 C>G · GRCh38: chr10:87933126 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.(His123Asp)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PTEN c.367C>G (p.His123Asp) variant has been observed in somatic cancers (COSMIC COSV64294365, n=3) and has been reported in ClinVar, including a pathogenic expert-panel classification.

2

This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, which is below the PTEN Expert Panel PM2 threshold for population rarity.

3

In the PTEN saturation mutagenesis phosphatase assay, p.His123Asp showed a high-confidence damaging result with cumulative fitness score -4.3458, which is below the PTEN Expert Panel PS3_Moderate threshold of <= -1.11.

4

Computational evidence supports a deleterious effect, with REVEL 0.98 above the PTEN Expert Panel PP3 threshold of >0.7 and BayesDel 0.601229 positive, while SpliceAI max delta 0.01 does not suggest splice disruption.

5

This variant also affects a PTEN catalytic motif residue and a different missense change at the same codon has been established as pathogenic, supporting PM1 and PM5 under the PTEN specification.

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	This is a missense variant, not a nonsense, frameshift, canonical +/-1 or 2 splice, or exon-level loss-of-function event, so the PTEN-specific PVS1 decision tree does not apply.	cspec pvs1_gene_context pvs1_variant_assessment vcep_pvs1_decisiontree_pten
PS1	Not met	No evidence was identified that this nucleotide change produces the same amino acid substitution as a previously established pathogenic variant through a different DNA change.	cspec clinvar
PS2	Not assessed	No confirmed de novo occurrence with documented maternity and paternity confirmation was identified.	cspec clinvar PMID:11918710
PS3	Met	In the PTEN saturation mutagenesis phosphatase assay, p.His123Asp had a cumulative fitness score of -4.3458 with a high-confidence result flag, which is below the PTEN Expert Panel PS3_Moderate threshold of <= -1.11 and supports a damaging effect on PTEN function.	cspec vcep_mmc2
PS4	Not assessed	This variant has been reported in ClinVar and in somatic cancer databases, but no case-control enrichment data or PTEN Expert Panel phenotype specificity score was identified to support PS4.	cspec clinvar oncokb
PM1	Met	This missense variant affects codon 123, which lies within the PTEN catalytic motif spanning residues 123-130 defined by the PTEN Expert Panel as a critical functional region for PM1.	cspec
PM2	Met	This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, which is below the PTEN Expert Panel PM2 threshold of <0.00001 (0.001%) and supports rarity in population databases.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	PM3 is not applicable in the PTEN Expert Panel framework for this disorder context.	cspec
PM4	N/A	This variant does not cause an in-frame insertion, in-frame deletion, or stop-loss event, so PM4 does not apply.	cspec
PM5	Met	A different missense change at the same residue, PTEN p.His123Arg, is established as pathogenic by expert panel review in ClinVar. The observed substitution p.His123Asp has a BLOSUM62 score of -1, which is equal to or more deleterious than the comparator p.His123Arg score of 0, meeting the PTEN Expert Panel PM5 rule.	cspec clinvar
PM6	Not assessed	No assumed de novo occurrence with the required phenotype and family-history context was identified.	cspec clinvar PMID:11918710
PP1	Not assessed	No segregation data were identified to show co-segregation with disease across informative meioses.	cspec clinvar
PP2	Met	This is a missense variant in PTEN, a gene for which the PTEN Expert Panel permits PP2 because missense variation is a recognized disease mechanism and benign missense variation is comparatively constrained.	cspec
PP3	Met	REVEL is 0.98, which is above the PTEN Expert Panel PP3 threshold of >0.7 and supports a deleterious missense effect. BayesDel is also positive at 0.601229, while SpliceAI shows a low maximum delta score of 0.01, which does not suggest a splice effect.	cspec revel bayesdel spliceai
PP4	N/A	PP4 is not applicable in the PTEN Expert Panel framework because phenotype specificity is incorporated into PS4 scoring.	cspec
PP5	Met	Expert panel Clingen PTEN Variant Curation Expert Panel, Clingen classified as Pathogenic.	cspec clinvar
BA1	Not met	This variant is absent from population databases and does not meet the PTEN Expert Panel BA1 threshold of >0.00056 (0.056%).	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	This variant is absent from population databases and does not meet the PTEN Expert Panel BS1 thresholds of 0.0000043 to 0.00056.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No homozygous observations in healthy or PTEN hamartoma tumor syndrome-unaffected individuals were identified.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not met	Available functional evidence does not show preserved PTEN function. Instead, the PTEN phosphatase assay showed a damaging result with cumulative fitness score -4.3458, so BS3 is not supported.	cspec vcep_mmc2
BS4	Not assessed	No data were identified showing lack of segregation in one or more affected families.	cspec clinvar
BP1	N/A	BP1 is not applicable in the PTEN Expert Panel framework.	cspec
BP2	Not assessed	No phase data were identified showing this variant in trans with a pathogenic PTEN variant or recurrently in cis/phase unknown with pathogenic PTEN variants.	cspec clinvar
BP3	N/A	BP3 is not applicable in the PTEN Expert Panel framework.	cspec
BP4	Not met	Computational evidence does not support a benign effect. REVEL is 0.98, which is above the PTEN Expert Panel benign threshold of <0.5 for missense variants.	cspec revel
BP5	Not assessed	No alternate highly penetrant molecular explanation with non-overlapping phenotype was identified to support BP5.	cspec
BP6	N/A	BP6 is not applicable in the PTEN Expert Panel framework.	cspec
BP7	N/A	This is not a synonymous or qualifying deep intronic variant, so BP7 does not apply.	cspec spliceai

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