Variant classification summary

NM_000314.8:c.802-29C>A

PTEN · NP_000305.3:p.? · NM_000314.8

GRCh37: chr10:89720622 C>A · GRCh38: chr10:87960865 C>A

Gene: PTEN Transcript: NM_000314.8

Final call

VUS

PM2 supporting BP7 supporting benign

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.?

gnomAD AF

0.0 (v4.1)

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000314.8:c.802-29C>A is absent from gnomAD v4.1 (0/1,512,514 alleles) and gnomAD v2.1, satisfying PM2 at supporting strength per the PTEN VCEP threshold of <0.001% allele frequency.

2

This intronic variant at position -29 from the exon 8 acceptor splice site is at or beyond the -21 threshold. SpliceAI predicts no splicing impact (max delta 0.01; DS_AG=0.0, DS_AL=0.01, DS_DG=0.01, DS_DL=0.0), satisfying BP7 at supporting strength per the PTEN VCEP.

3

No pathogenic or benign criteria at moderate or higher strength are met. With one pathogenic supporting criterion (PM2_Supporting) and one benign supporting criterion (BP7), the variant is classified as a Variant of Uncertain Significance (VUS).

4

The variant has not been reported in ClinVar, COSMIC, or the published literature. No functional studies, segregation data, de novo observations, or case-control data are available.

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	This variant is a deep intronic substitution at c.802-29 (29 bases upstream of exon 8), not a canonical ±1,2 splice site disruption. The PTEN VCEP PVS1 decision tree (PVS1_DecisionTree_PTEN.pdf) only covers nonsense, frameshift, canonical GT-AG splice site disruptions, and single/multi-exon deletions. Deep intronic variants are not within scope of the PTEN PVS1 framework.	vcep_pvs1_decisiontree_pten
PS1	N/A	PS1 requires the same amino acid change as a previously established pathogenic variant regardless of nucleotide change, or a different variant at the same nucleotide position as a known pathogenic splicing variant. This is an intronic variant at c.802-29 with no known protein consequence (NP_000305.3:p.?). There is no amino acid change to compare and no established pathogenic variant at this nucleotide position.
PS2	Not met	No de novo observations have been reported for this variant. The variant is absent from ClinVar and no literature reports de novo occurrence in a patient with PHTS and no family history.	clinvar
PS3	Not met	No functional assay data is available for this intronic variant. The PTEN VCEP specifies PS3 for RNA/mini-gene splicing assays (PS3_Strong) or phosphatase activity ≤ -1.11 per Mighell et al. 2018 (PS3_Moderate). The mmc2.xlsx (Mighell et al. saturation mutagenesis) is restricted to missense variants and does not apply to intronic variants. SpliceAI (max delta 0.01) is an in silico prediction tool, not a functional assay, and does not meet PS3 requirements.	spliceai vcep_mmc2
PS4	Not met	No proband data or case-control studies are available for this variant. The variant is absent from ClinVar with zero submissions, and no published proband counts or specificity scores are available.	clinvar
PS5	N/A	PS5 is not a standard ACMG/AMP 2015 criterion and is not defined in the ClinGen PTEN Expert Panel Specifications v3.2. This intronic variant has no protein-level comparator to assess.
PM1	N/A	PM1 per PTEN VCEP requires location in a catalytic motif at residues 90-94, 123-130, or 166-168 (NP_000305.3). This is an intronic variant at c.802-29 with no defined amino acid position. The variant does not alter any protein residue and SpliceAI predicts no splicing impact (max delta 0.01), so it does not disrupt any functional domain.	spliceai
PM2	Met	This variant is absent from gnomAD v2.1 and v4.1 (0/1,512,514 alleles across all populations). The PTEN VCEP specifies PM2 at supporting strength when allele frequency is <0.001% (0.00001). The observed AF of 0 satisfies this threshold.	gnomad_v2 gnomad_v4
PM5	N/A	PM5 per PTEN VCEP requires a missense change at an amino acid residue where a different missense change has been determined to be pathogenic or likely pathogenic. This is an intronic variant with no amino acid change. The pm5_candidates.json confirms the variant class is not missense-like and is not eligible for classic same-residue PM5.
PM6	Not met	No de novo observations have been reported for this variant. The variant is absent from ClinVar and no literature reports assumed or confirmed de novo occurrence in a patient with PHTS and no family history.	clinvar
PP1	Not met	No co-segregation data is available for this variant. The PTEN VCEP requires at least 3-4 meioses for supporting-level PP1. No family studies or segregation analyses have been reported.
PP2	N/A	PP2 is restricted to missense variants in a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease. This variant is intronic (c.802-29C>A), not a missense variant.
PP3	Not met	PP3 per PTEN VCEP requires multiple lines of computational evidence supporting a deleterious effect. For splicing variants, concordance of SpliceAI and VarSeak is required. SpliceAI predicts no splicing impact (max delta 0.01, all individual delta scores ≤0.01). No in silico tool predicts a deleterious effect on the gene product.	spliceai
PP4	N/A	PP4 is designated as Not Applicable by the ClinGen PTEN Expert Panel. Phenotype specificity has been incorporated into PS4 rule specifications.	cspec
PP5	N/A	PP5 is designated as Not Applicable by the ClinGen PTEN Expert Panel. Additionally, this variant is absent from ClinVar entirely, so no expert panel pathogenic classification exists to cite.	cspec clinvar
BA1	Not met	The PTEN VCEP BA1 threshold is a filtering allele frequency >0.056% (0.00056) in gnomAD. This variant is absent from gnomAD v2.1 and v4.1 (AF = 0.00000%, 0/1,512,514 alleles). The allele frequency is well below the BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	The PTEN VCEP BS1 threshold is an allele frequency from 0.0043% (strong) or 0.00043% (supporting) up to 0.056%. This variant is absent from gnomAD (AF = 0.00000%). The allele frequency is below even the supporting threshold.	gnomad_v2 gnomad_v4
BS2	Not met	The PTEN VCEP BS2 requires observation in the homozygous state in a healthy or PHTS-unaffected individual. This variant is absent from gnomAD (0 homozygotes) and has no reported homozygous observations in any database.	gnomad_v4
BS3	Not met	The PTEN VCEP BS3_Strong requires an RNA, mini-gene, or other splicing assay demonstrating no splicing impact for intronic variants. The VCEP BS3_Supporting requires phosphatase activity >0 per Mighell et al. 2018, which applies only to missense variants. No functional assay data is available for this variant. SpliceAI (max delta 0.01) is an in silico tool and does not constitute a functional assay.	spliceai vcep_mmc2
BS4	Not met	No segregation data is available for this variant. The PTEN VCEP BS4 requires lack of segregation in affected members of one family (supporting) or two or more families (strong). No family studies have been reported.
BP1	N/A	BP1 is designated as Not Applicable by the ClinGen PTEN Expert Panel. BP1 applies to truncating variants in genes where loss of function is not a known disease mechanism, which does not apply to PTEN.	cspec
BP2	Not met	The PTEN VCEP BP2 requires observation in trans with a pathogenic or likely pathogenic PTEN variant, or at least three observations in cis/unknown phase with different pathogenic/likely pathogenic PTEN variants. No such observations have been reported for this variant.
BP4	Not met	The PTEN VCEP BP4 requires concordance of SpliceAI and VarSeak in silico models predicting no splicing impact for intronic variants. SpliceAI predicts no impact (max delta 0.01, within the benign 0-0.2 range). However, VarSeak data is not available, and the VCEP requires concordance of both tools. Without VarSeak, the criterion cannot be fully applied.	spliceai
BP5	Not met	The PTEN VCEP BP5 requires the variant to be found in at least two cases with an alternate molecular basis for disease, where the other gene/disorder is highly penetrant and the patient's personal/family history shows no overlap with PTEN. No such cases have been reported for this variant.
BP6	N/A	BP6 is designated as Not Applicable for this VCEP by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Additionally, this variant is absent from ClinVar, so no reputable source has reported it as benign.	cspec
BP7	Met	This is an intronic variant at c.802-29, which is beyond the -21 position from the exon 8 splice acceptor. SpliceAI predicts no impact to the splice consensus sequence and no creation of a new splice site (max delta 0.01, with individual delta scores: DS_AG=0.0, DS_AL=0.01, DS_DG=0.01, DS_DL=0.0). The PTEN VCEP BP7 applies at supporting level for intronic variants at or beyond +7/-21 where splicing prediction algorithms predict no impact.	spliceai

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