Variant classification summary

NM_000314.8:c.1027-2A>C

PTEN · NP_000305.3:p.? · NM_000314.8

GRCh37: chr10:89725042 A>C · GRCh38: chr10:87965285 A>C

Gene: PTEN Transcript: NM_000314.8

Final call

Pathogenic

PVS1 very strong PS3 strong PM2 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.?

gnomAD AF

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000314.8:c.1027-2A>C disrupts the canonical AG splice-acceptor of exon 9 (intron 8, -2 position), 5' to the p.D375 (c.1121) threshold, and is assigned PVS1 at very strong strength under the ClinGen PTEN Expert Panel PVS1 decision tree.

2

RNA analysis in patient-derived cells (RT-PCR and 3'RACE) demonstrated that this exact variant causes premature transcript termination within exon 8 at r.962 with polyadenylation, producing p.(Thr321_403del), meeting PS3 at strong strength.

3

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting PM2 at supporting strength.

4

The variant has been reported in ClinVar as Pathogenic by three clinical laboratories and Likely pathogenic by one clinical laboratory, consistent with a pathogenic interpretation.

5

PVS1 alone (one very strong pathogenic criterion) satisfies the ClinGen PTEN Expert Panel combination rules for a Pathogenic classification.

Final determination: Rule1 in the ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.2 v3.2 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as 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	Met	NM_000314.8:c.1027-2A>C disrupts the canonical AG splice-acceptor of exon 9 (intron 8, -2 position), a GT-AG 1,2 splice site 5' to p.D375 (c.1121). Under the ClinGen PTEN Expert Panel PVS1 decision tree this is assigned full PVS1, and functional RNA analysis confirms abnormal transcript termination producing p.(Thr321_403del).	vcep_pvs1_decisiontree_pten pvs1_variant_assessment pvs1_gene_context PMID:28677221
PS1	Not met	No established pathogenic variant at the same nucleotide position (c.1027-2) with a different nucleotide change was identified to satisfy the PS1 'same nucleotide position' rule.
PS2	Not met	No confirmed de novo observation (maternity and paternity confirmed) for this variant was read in the literature. A ClinVar submission with origin 'de novo' exists but no specific de novo report was reviewed.
PS3	Met	Well-established RNA functional assay in patient-derived cells (RT-PCR and 3'RACE) demonstrated that this exact variant causes premature transcript termination within exon 8 at r.962 with polyadenylation, producing p.(Thr321_403del). This meets PTEN EP PS3 at strong strength (RNA assay showing impact on splicing).	PMID:28677221 cspec
PS4	Not met	No case-control data, odds ratio, or proband specificity score establishing significantly increased prevalence of this variant in affected individuals was available.
PS5	N/A	PS5 is not a criterion defined in the ClinGen PTEN Expert Panel specifications v3.2 nor in the standard ACMG/AMP 2015 criteria.
PM1	Not met	The PTEN EP PM1 is defined for residues in the catalytic motifs (90-94, 123-130, 166-168). This variant is a splice-acceptor substitution at c.1027-2, not located within a catalytic motif residue range.
PM2	Met	The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the PTEN EP PM2 threshold (allele frequency <0.00001 / 0.001%).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	PM5 applies to missense changes at a residue with an established pathogenic missense variant. This variant is a canonical splice-site substitution, not a missense change.
PM6	Not met	No assumed de novo observation for this variant was read in the literature. A ClinVar submission with origin 'de novo' exists but the specific report was not reviewed.
PP1	Not met	No co-segregation data (meioses) in affected family members was available for this variant.
PP2	N/A	PP2 applies to missense variants in a gene with a low rate of benign missense variation. This is a splice-site variant, not a missense variant.
PP3	Not met	The splice-effect prediction (SpliceAI max delta 0.994) is already captured by PVS1 and should not be double-counted. The PTEN EP PP3 rule additionally requires concordance of SpliceAI and VarSeak, and VarSeak was not available.	spliceai
PP4	N/A	The ClinGen PTEN Expert Panel marks PP4 as Not Applicable; phenotype specificity is incorporated into the PS4 Use 2 specification.	cspec
PP5	N/A	The ClinGen PTEN Expert Panel marks PP5 as Not Applicable, and the ClinVar record is 'criteria provided, single submitter' (no 3-star expert panel review), so the global PP5 supporting rule does not apply.
BA1	Not met	The variant is absent from gnomAD, far below the BA1 filtering allele frequency threshold (>0.00056 / 0.056%).	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from gnomAD, not present at the BS1 allele frequency range (0.000043-0.00056).	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No homozygous observations in a healthy or PHTS-unaffected individual were identified.
BS3	Not met	Functional RNA analysis demonstrates a damaging effect on splicing (premature transcript termination), which is inconsistent with BS3. No functional study showing no damaging effect was identified.	PMID:28677221
BS4	Not met	No lack-of-segregation data in affected family members was available.
BP1	N/A	The ClinGen PTEN Expert Panel marks BP1 as Not Applicable.
BP2	Not met	No observation of this variant in trans (or three observations in cis/unknown phase) with a pathogenic or likely pathogenic PTEN variant was identified.
BP4	Not met	SpliceAI predicts splice impact (max delta 0.994), inconsistent with a benign computational prediction. The variant is a canonical splice-site disruption, not a benign splicing variant.	spliceai
BP5	Not met	No case with an alternate molecular basis for disease was identified.
BP6	N/A	The ClinGen PTEN Expert Panel marks BP6 as Not Applicable for this VCEP, and the variant is not reported as benign by a reputable source.
BP7	Not met	BP7 requires an intronic variant at or beyond +7/-21 with no predicted splice impact. This variant is at the canonical -2 splice-acceptor position with SpliceAI-predicted impact, so BP7 does not apply.	spliceai
BP3	N/A	BP3 applies to in-frame indels in non-repeat regions; this is a splice-site substitution.
PM3	N/A	PM3 applies to recessive disorders; PTEN hamartoma tumor syndrome is autosomal dominant.
PM4	N/A	PM4 applies to protein length changes from in-frame indels or stop-loss; this is a canonical splice-site substitution.

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