Variant classification summary

NM_000314.8:c.368A>G

PTEN · NP_000305.3:p.(His123Arg) · NM_000314.8

GRCh37: chr10:89692884 A>G · GRCh38: chr10:87933127 A>G

Gene: PTEN Transcript: NM_000314.8

Final call

Likely Pathogenic

PS3 moderate PM1 moderate PM2 supporting PM6 moderate PP2 supporting PP3 supporting PP5 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(His123Arg)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

c.368A>G (p.His123Arg) is a missense variant in exon 5 of PTEN, within the phosphatase catalytic motif (residues 123-130).

2

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2_Supporting under PTEN VCEP rules.

3

His123 is located within the VCEP-defined catalytic motif, meeting PM1_Moderate.

4

The variant has been classified as Pathogenic by the ClinGen PTEN Variant Curation Expert Panel (ClinVar SCV000863477, reviewed by expert panel).

5

In the Mighell et al. 2018 (PMID:29706350) saturation mutagenesis phosphatase activity assay, H123R has a cumulative fitness score of -3.83 (High_conf = True), meeting the PTEN VCEP threshold for PS3_Moderate (Cum_score <= -1.11).

6

The ClinGen PTEN VCEP applied PM6_Moderate, noting an assumed de novo occurrence (parentage unconfirmed) in a patient with Cowden syndrome (Nelen et al. 1999, PMID:10234502).

7

Computational evidence supports pathogenicity: REVEL score 0.985 meets PP3_Supporting; PTEN's low rate of benign missense variation supports PP2_Supporting.

8

The ClinGen PTEN VCEP classification as Pathogenic supports PP5_Supporting, applied per user directive to override VCEP Not Applicable when expert panel classification exists.

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	c.368A>G is a missense variant (p.His123Arg). The PTEN PVS1 decision tree (VCEP v3.2.0) applies only to null variants (nonsense, frameshift, canonical GT-AG splice site disruptions, and exon-level CNVs). Missense variants do not qualify for PVS1 adjudication under this framework.	cspec
PS1	Not met	PS1 requires the same amino acid change as a previously established pathogenic variant regardless of nucleotide change. No evidence was found of p.His123Arg caused by a different nucleotide substitution with a prior pathogenic classification.
PS2	Not assessed	ClinVar submissions (SCV004103762, SCV000617322) and the ClinGen PTEN VCEP (SCV000863477) reference a de novo occurrence in Nelen et al. 1999 (PMID:10234502). The VCEP applied PM6 (assumed de novo, unconfirmed parentage) rather than PS2 (confirmed de novo). Full text of PMID:10234502 was not available for independent confirmation. Without direct verification of the de novo report, PS2 cannot be assessed independently.	clinvar
PS3	Met	PTEN H123R (His123Arg) has a cumulative fitness score (Cum_score) of -3.83 in the Mighell et al. 2018 (PMID:29706350) saturation mutagenesis phosphatase activity assay. This score is ≤ -1.11, meeting the PTEN VCEP threshold for PS3_Moderate. The measurement is high-confidence (High_conf = True, Pass SE Filter).	cspec vcep_mmc2
PS4	Not assessed	PS4 requires variant-specific proband counts with phenotype specificity scores. No proband counts or phenotype specificity data were available for this variant in the evidence packet.
PS5	Not assessed	No independent evidence was identified to support PS5. This criterion is typically used for variants where additional independent data confirm pathogenicity beyond what other criteria capture.
PM1	Met	Residue His123 is located within the PTEN phosphatase catalytic motif defined by the VCEP as residues 123-130 (NP_000305.3). This meets the PTEN VCEP PM1_Moderate criterion for missense variants located in a critical functional domain.	cspec
PM2	Met	c.368A>G is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Per PTEN VCEP rules, absence from large sequenced population databases (< 0.001% allele frequency) meets PM2_Supporting.	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM5	Not assessed	PM5 requires a different pathogenic or likely pathogenic missense variant at the same amino acid residue (His123). The pipeline did not identify any comparator missense variants at His123 with P/LP classification. Without a validated comparator, PM5 cannot be applied.
PM6	Met	The ClinGen PTEN Variant Curation Expert Panel (SCV000863477) explicitly applied PM6 at the Moderate level, noting 'assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history.' This expert panel determination is followed directly. The de novo observation is referenced to Nelen et al. 1999 (PMID:10234502).	clinvar cspec
PP1	Not assessed	No co-segregation data were available for this variant. PP1 requires observation of co-segregation with disease in multiple affected family members across a specified number of meioses.
PP2	Met	PTEN is a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease. Per PTEN VCEP rules, PP2_Supporting applies to missense variants.	cspec
PP3	Met	REVEL score is 0.985, which exceeds the PTEN VCEP PP3 threshold of > 0.7 for missense variants. SpliceAI predicts no splicing impact (max delta = 0.01), consistent with a missense mechanism rather than splicing defect. BayesDel score of 0.61462 also supports a deleterious prediction.	revel spliceai bayesdel cspec
PP4	N/A	The PTEN VCEP designates PP4 as Not Applicable. Phenotype specificity is incorporated into PS4 rule specifications instead.	cspec
PP5	Met	Expert panel Clingen PTEN Variant Curation Expert Panel, Clingen classified as Pathogenic.	clinvar cspec
BA1	Not met	c.368A>G is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The PTEN VCEP BA1 threshold requires filtering allele frequency > 0.056%. The variant does not meet this threshold.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS1	Not met	c.368A>G is absent from gnomAD. The PTEN VCEP BS1 threshold requires filtering allele frequency from 0.000043 (0.0043%) to 0.00056 (0.056%). The variant's allele frequency of 0 does not fall within the BS1 benign range.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS2	Not assessed	BS2 requires observation in the homozygous state in a healthy or PHTS-unaffected individual. No homozygous observations were reported in gnomAD or other sources.
BS3	Not met	PTEN H123R has a Cum_score of -3.83 in the Mighell et al. 2018 functional assay (PMID:29706350). BS3 requires phosphatase activity > 0 (BS3_Supporting) or a well-established functional study showing no damaging effect (BS3). The Cum_score is strongly negative, indicating damaging effect, which contradicts the benign evidence required for BS3.	vcep_mmc2 cspec
BS4	Not assessed	BS4 requires lack of segregation in affected family members (two or more families for Strong, one family for Supporting). No segregation data were available for this variant.
BP1	N/A	The PTEN VCEP designates BP1 as Not Applicable.	cspec
BP2	Not assessed	BP2 requires observation in trans with a pathogenic/likely pathogenic PTEN variant or at least three observations in cis/phase unknown. No such observations were available.
BP3	N/A	c.368A>G is a single-nucleotide substitution, not an in-frame deletion or insertion. BP3 applies only to in-frame indels in non-repeat regions.
BP4	Not met	BP4 requires multiple lines of computational evidence suggesting no impact on the gene product. For missense variants per PTEN VCEP, REVEL score < 0.5 is required. REVEL for c.368A>G is 0.985, strongly predicting a damaging effect. BayesDel (0.615) also supports a deleterious prediction.	revel bayesdel cspec
BP5	Not assessed	BP5 requires a variant found in a case with an alternate molecular basis for disease where the other gene/disorder is highly penetrant and the patient's history does not overlap with PTEN. No such case was identified.
BP6	N/A	The PTEN VCEP designates BP6 as Not Applicable.	cspec
BP7	N/A	c.368A>G is a missense variant, not a synonymous (silent) or intronic variant. BP7 applies only to synonymous and deep intronic variants.
PM3	N/A	The PTEN VCEP designates PM3 as Not Applicable.
PM4	N/A	c.368A>G is a missense substitution, not an in-frame deletion/insertion or stop-loss variant. PM4 applies to protein length changes from in-frame indels or stop-loss variants.

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