Variant classification summary

NM_000314.8:c.413A>G

PTEN · NP_000305.3:p.(Tyr138Cys) · NM_000314.8

GRCh37: chr10:89692929 A>G · GRCh38: chr10:87933172 A>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.(Tyr138Cys)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000314.8:c.413A>G (p.Tyr138Cys) is a missense variant in exon 5 of PTEN. It is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada), satisfying PM2_Supporting per PTEN VCEP criteria.

2

Functional evidence from Mighell et al. 2018 (PMID:29706350) saturation mutagenesis demonstrates that Y138C has a cumulative fitness score of -1.766, meeting the PTEN VCEP threshold of ≤ -1.11 for PS3_Moderate. Independently, Tibarewal et al. 2012 (PMID:22375056) characterized Y138C and demonstrated that it retains lipid phosphatase activity but selectively lacks protein phosphatase activity, with failure to suppress cellular invasion — confirming a damaging functional effect.

3

Computational evidence supports pathogenicity: REVEL score 0.962 (>0.7, meeting PP3 threshold per PTEN VCEP). PTEN has a low rate of benign missense variation and missense variants are a known disease mechanism for PTEN hamartoma tumor syndrome (PP2 per VCEP).

4

The variant is classified as Uncertain Significance in ClinVar (variation ID 486230) by all four submitting clinical laboratories. It has been observed in somatic cancers (COSMIC, n=6).

5

Applying the PTEN VCEP classification rules: 1 moderate pathogenic criterion (PS3_Moderate) and 3 supporting pathogenic criteria (PM2_Supporting, PP2, PP3) are met. No benign criteria are met. Per the VCEP combination rules, this evidence profile does not reach the Likely Pathogenic threshold (requires ≥3 moderate, or 2 moderate + ≥2 supporting, or 1 strong + 1 moderate, or 1 moderate + ≥4 supporting). The variant is classified as a Variant of Uncertain Significance (VUS).

6

Key gap: the Mighell et al. functional data for Y138C has a High_conf=False quality flag ('Fail Both'), indicating the measurement did not pass high-confidence filters. Additional functional validation, segregation data, de novo observations, or clinical case-level phenotype data could resolve this VUS.

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	NM_000314.8:c.413A>G is a missense variant (p.Tyr138Cys); the PTEN VCEP PVS1 decision tree applies only to null variants (nonsense, frameshift, canonical splice site, CNV) and this variant does not fall into any of those buckets.	pvs1_variant_assessment pvs1_gene_context cspec
PS1	Not met	PS1 requires that the same amino acid change (p.Tyr138Cys) has been previously established as pathogenic. In ClinVar (variation ID 486230), NM_000314.8:c.413A>G (p.Tyr138Cys) is classified as Uncertain Significance by all submitters. No prior pathogenic classification for this amino acid change exists.	clinvar cspec
PS2	Not assessed	No de novo observation data is available in the evidence packet. None of the reviewed publications report a de novo occurrence of NM_000314.8:c.413A>G.
PS3	Met	Per PTEN VCEP specifications, PS3_Moderate is applied when phosphatase activity cumulative fitness score (Cum_score) ≤ -1.11 in the Mighell et al. 2018 (PMID:29706350) saturation mutagenesis assay. Y138C has a Cum_score of -1.766 in Table S2, meeting this threshold. Independently, Tibarewal et al. 2012 (PMID:22375056) directly characterized Y138C, demonstrating retained lipid phosphatase activity with selective loss of protein phosphatase activity and failure to suppress cellular invasion — consistent with a damaging functional effect.	vcep_mmc2 PMID:22375056 cspec
PS4	Not assessed	No proband counts or case-control data are available to calculate a PTEN specificity score under the VCEP PS4 framework. The variant has been observed in ClinVar (4 clinical laboratory submissions, all VUS) and COSMIC (6 somatic occurrences), but these do not constitute proband data suitable for PS4 scoring.	clinvar
PS5	N/A	PS5 is not a standard ACMG/AMP criterion and is not included in the PTEN VCEP specifications.	cspec
PM1	Not met	Per PTEN VCEP specifications, PM1 is restricted to residues within the defined catalytic motifs: 90-94, 123-130, and 166-168 (NP_000305.3). p.Tyr138 (position 138) lies outside these specified ranges. Although the variant lies in a statistically significant hotspot (cancerhotspots.org) and position 138 is within the phosphatase domain critical for protein phosphatase activity, the VCEP definition does not include residue 138.	cspec
PM2	Met	Per PTEN VCEP specifications, PM2_Supporting is applied when the variant is absent from population databases at allele frequency < 0.00001 (0.001%). NM_000314.8:c.413A>G is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM5	Not met	PM5 requires a different pathogenic or likely pathogenic missense change at the same amino acid residue (p.Tyr138). The PM5 candidate search identified no pathogenic/likely pathogenic missense variants at residue 138 in ClinVar. The only other missense variant identified at this position (Y138A in Mighell et al. Table S2) is not classified as pathogenic in ClinVar.	pm5_candidates clinvar
PM6	Not assessed	No de novo occurrence data is available in the evidence packet. None of the reviewed publications report a de novo observation of NM_000314.8:c.413A>G.
PP1	Not assessed	No co-segregation data is available. None of the reviewed publications report family studies or meiotic segregation data for NM_000314.8:c.413A>G.
PP2	Met	Per PTEN VCEP specifications, PP2 applies to missense variants in PTEN, 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 with an observed deficit of benign missense variation and an established role for missense mutations in PHTS.	cspec
PP3	Met	Per PTEN VCEP specifications, PP3 is applied for missense variants when REVEL score > 0.7. The REVEL score for NM_000314.8:c.413A>G (p.Tyr138Cys) is 0.962, substantially exceeding the 0.7 threshold. BayesDel score is 0.518. SpliceAI max delta score is 0.00 (no predicted splicing impact).	revel bayesdel spliceai cspec
PP4	N/A	The PTEN VCEP explicitly states PP4 is Not Applicable; phenotype specificity has been incorporated into the PS4 rule specifications.	cspec
PP5	N/A	The PTEN VCEP explicitly states PP5 is Not Applicable. Additionally, ClinVar review status is 'criteria provided, single submitter' (1-star), which would not meet the 3-star expert panel threshold required for PP5 application even under generic ACMG/AMP.	cspec clinvar
BA1	Not met	Per PTEN VCEP, BA1 requires gnomAD filtering allele frequency > 0.00056 (0.056%). NM_000314.8:c.413A>G is absent from all gnomAD datasets (v2.1, v4.1, gnomAD-Canada).	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS1	Not met	Per PTEN VCEP, BS1 requires gnomAD filtering allele frequency from 0.000043 (0.0043%) to 0.00056 (0.056%). NM_000314.8:c.413A>G is absent from all gnomAD datasets, falling below the BS1 frequency range.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS2	Not met	Per PTEN VCEP, BS2 requires observation in the homozygous state in a healthy or PHTS-unaffected individual. No homozygous observations are reported in gnomAD or the literature for NM_000314.8:c.413A>G.	gnomad_v2 gnomad_v4 cspec
BS3	Not met	BS3 requires functional studies showing no damaging effect on protein function. The available functional data (Mighell et al. 2018 saturation mutagenesis, Cum_score = -1.766 ≤ -1.11; Tibarewal et al. 2012 showing loss of protein phosphatase activity and failure to suppress invasion) demonstrate a damaging effect, not a benign one. Per the PTEN VCEP, BS3_Supporting requires phosphatase activity > 0 — the observed Cum_score of -1.766 contradicts this.	vcep_mmc2 PMID:22375056 cspec
BS4	Not assessed	No segregation data is available. None of the reviewed publications report family studies or lack of segregation for NM_000314.8:c.413A>G.
BP1	N/A	The PTEN VCEP explicitly states BP1 is Not Applicable.	cspec
BP2	Not met	Per PTEN VCEP, BP2 requires observation in trans with a pathogenic or likely pathogenic PTEN variant, or at least three observations in cis/phase unknown with different pathogenic/likely pathogenic PTEN variants. No such observations are reported for NM_000314.8:c.413A>G.	cspec
BP4	Not met	Per PTEN VCEP, BP4 is applied for missense variants when REVEL score < 0.5 (multiple lines of computational evidence suggest no impact). The REVEL score for NM_000314.8:c.413A>G is 0.962, which is above the 0.5 threshold and indicates a damaging prediction, not a benign one.	revel bayesdel cspec
BP5	Not assessed	BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such data is available for NM_000314.8:c.413A>G.
BP6	N/A	The PTEN VCEP explicitly states BP6 is Not Applicable.	cspec
BP7	N/A	BP7 applies only to synonymous (silent) or intronic variants at or beyond +7/-21 for which splicing prediction algorithms predict no impact. NM_000314.8:c.413A>G is a missense variant and is not eligible for BP7.	cspec

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