Variant classification summary

NM_000314.8:c.532T>G

PTEN · NP_000305.3:p.(Tyr178Asp) · NM_000314.8

GRCh37: chr10:89711914 T>G · GRCh38: chr10:87952157 T>G

Gene: PTEN Transcript: NM_000314.8

Final call

VUS

PS3 moderate PM2 supporting PP2 supporting PP3 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Tyr178Asp)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000314.8:c.532T>G (p.Tyr178Asp) is a missense variant in PTEN exon 6. This variant is absent from gnomAD v2.1 and v4.1 population databases (PM2_Supporting).

2

Functional assessment via saturation mutagenesis phosphatase activity assay (Mighell et al. 2018, PMID: 29706350) demonstrates a cumulative fitness score of -4.72, well below the VCEP PS3_Moderate threshold of <= -1.11, with high-confidence measurement (PS3_Moderate).

3

Computational predictions support a deleterious effect: REVEL score of 0.958 exceeds the VCEP PP3 threshold of > 0.7 (PP3). PTEN has a low rate of benign missense variation and missense variants are a common disease mechanism (PP2).

4

This variant has been reported in ClinVar as Uncertain significance by a single submitter (VCV000945254) and in COSMIC as a somatic variant (COSV64304856, n=1). OncoKB classifies it as Likely Oncogenic in the somatic context.

5

Position 178 is outside the VCEP-defined PM1 catalytic motifs (WPD loop 90-94, P-loop 123-130, TI-loop 166-168). No alternate pathogenic missense at residue 178 was identified for PM5. No de novo, cosegregation, or case-control data are available.

6

Applying the PTEN VCEP v3.2 combination rules: one moderate criterion (PS3_Moderate) and three supporting criteria (PM2_Supporting, PP2, PP3) are met. No combination rule for Likely Pathogenic is satisfied (Rule 13 requires >=3 moderate; Rule 14 requires 2 moderate + >=2 supporting; Rule 15 requires 1 moderate + >=4 supporting). The variant is classified as Uncertain Significance.

Final determination: No criteria-combination rule matched the adjudicated criteria in the ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.2 v3.2 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	PVS1 applies only to null variants (nonsense, frameshift, canonical splice site, CNV) per the PTEN VCEP decision tree. NM_000314.8:c.532T>G is a missense variant (p.Tyr178Asp) and does not qualify.	vcep_pvs1_decisiontree_pten
PS1	Not met	PS1 requires the same amino acid change (Tyr178Asp) to have been previously established as pathogenic from a different nucleotide change. No evidence of a pathogenic Y178D from an alternate nucleotide was identified in ClinVar or the PTEN VCEP database.	clinvar cspec
PS2	Not met	No de novo observation data are available for this variant. PS2 requires confirmed or assumed de novo occurrence in a patient with disease and no family history.
PS3	Met	Y178D (Tyr178Asp) has a cumulative fitness score of -4.72 in the Mighell et al. 2018 (PMID: 29706350) saturation mutagenesis phosphatase activity assay, well below the PTEN VCEP PS3_Moderate threshold of <= -1.11. The measurement is flagged as high confidence (High_conf=True). This constitutes well-established in vitro functional evidence of a damaging effect on phosphatase activity.	vcep_mmc2 cspec
PS4	Not met	PS4 requires proband specificity scores or significantly increased prevalence in affected individuals. No proband data or case-control study data are available for this variant.	clinvar
PS5	N/A	PS5 is not defined in the ClinGen PTEN Expert Panel Specifications v3.2. In VCEP mode, criteria not established by the expert panel are not applicable.	cspec
PM1	Not met	The PTEN VCEP defines PM1 for residues in catalytic motifs: WPD loop (90-94), P-loop (123-130), and TI-loop (166-168). Position 178 (Tyr178) lies 12 residues C-terminal to the TI-loop and is not within any VCEP-defined PM1 domain. CancerHotspots.org identifies this residue as statistically significant, but the VCEP specification is authoritative and does not include residue 178.	cspec
PM2	Met	NM_000314.8:c.532T>G is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the PTEN VCEP PM2_Supporting threshold of allele frequency < 0.001% (0.00001).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	PM5 requires a different missense change at the same residue (Tyr178) with established pathogenic or likely pathogenic classification, with the variant under assessment having an equal or lower BLOSUM62 score. The only other missense at position 178 in the PTEN ClinVar dataset (Table S3) is Y178C (c.533A>G), classified as Uncertain significance. No P/LP missense comparator at residue 178 was identified.	vcep_mmc2 pm5_candidates
PM6	Not met	No assumed or confirmed de novo data are available for this variant. PM6 requires de novo observation without confirmation of paternity and maternity.
PP1	Not met	No cosegregation data are available for this variant. PP1 requires cosegregation with disease in multiple affected family members with at least 3 meioses.
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. This missense variant (Tyr178Asp) meets the PTEN VCEP PP2 criterion.	cspec
PP3	Met	REVEL score of 0.958 exceeds the PTEN VCEP PP3 threshold of > 0.7 for missense variants, indicating multiple lines of computational evidence support a deleterious effect.	revel cspec
PP4	N/A	PP4 is not applicable per PTEN VCEP v3.2. Phenotype specificity has been incorporated into the PS4 rule specifications.	cspec
PP5	N/A	PP5 is not for use per the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation, as stated in the PTEN VCEP v3.2.	cspec
BA1	Not met	BA1 requires filtering allele frequency > 0.056% in gnomAD. This variant is absent from gnomAD v2.1 and v4.1.	gnomad_v2 gnomad_v4
BS1	Not met	BS1 requires filtering allele frequency of 0.00043%-0.056% in gnomAD. This variant is absent from population databases.	gnomad_v2 gnomad_v4
BS2	Not met	BS2 requires observation in the homozygous state in a healthy or PHTS-unaffected individual. No homozygous observations are reported for this variant.	gnomad_v2 gnomad_v4
BS3	Not met	BS3_Supporting requires phosphatase activity > 0 per Mighell et al. 2018. Y178D has a cumulative fitness score of -4.72, indicating damaging effect, not benign. BS3_Strong does not apply as it is limited to splicing assays for intronic/synonymous variants.	vcep_mmc2
BS4	Not met	No lack of segregation data are available for this variant. BS4 requires lack of segregation in affected members of one or more families.
BP1	N/A	BP1 is not applicable to PTEN per the VCEP v3.2 specification. This criterion applies only to genes where primarily truncating variants cause disease, which is not the case for PTEN.	cspec
BP2	Not met	No evidence of this variant observed in trans with a P/LP PTEN variant or in cis with different P/LP PTEN variants.
BP4	Not met	BP4 for missense variants requires REVEL score < 0.5 per PTEN VCEP. The REVEL score for this variant is 0.958, well above the BP4 threshold.	revel cspec
BP5	Not met	No evidence that this variant has been found in a case with an alternate molecular basis for disease. BP5 requires at least two such cases per PTEN VCEP specification.
BP6	N/A	BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee, per PTEN VCEP v3.2.	cspec
BP7	N/A	BP7 applies only to synonymous (silent) or intronic variants. NM_000314.8:c.532T>G is a missense variant (p.Tyr178Asp).	cspec

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