Variant classification summary

NM_000314.8:c.492+14dup

PTEN · NP_000305.3:p.? · NM_000314.8

GRCh37: chr10:89693016 A>AT · GRCh38: chr10:87933259 A>AT

Gene: PTEN Transcript: NM_000314.8

Final call

Likely Benign

BS1 strong benign BP7 supporting benign

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.?

gnomAD AF

2.4976397304547203e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BS1_Strong is met: the gnomAD v4.1 grpmax filtering allele frequency is 5.81e-05 (0.0058%), which falls within the PTEN VCEP BS1_Strong range of 0.0043%-0.056%. This population frequency is higher than expected for a fully penetrant pathogenic PTEN variant causing PHTS.

2

BP7_Supporting is met: c.492+14dup is an intronic variant at position +14 (beyond +7). SpliceAI predicts no significant splice impact (max delta score 0.03) and no creation of a cryptic splice site, meeting the PTEN VCEP BP7 criteria.

3

PM2_Supporting is not met: although the overall gnomAD allele frequency is very low (v4.1: 0.00025%), the Middle Eastern subpopulation in gnomAD v4.1 has 2 alleles out of 6,068 (AF 0.033%), which exceeds the PTEN VCEP subpopulation threshold of 0.002% for multiple alleles.

4

PVS1 is not met: this intronic duplication at c.492+14 does not qualify as a null variant under the PTEN PVS1 decision tree, and SpliceAI predicts no splice disruption.

5

Combined classification: 1 strong benign criterion (BS1) + 1 supporting benign criterion (BP7) yields a classification of Likely Benign per the ACMG/AMP combining rules adopted by the PTEN VCEP.

Final determination: Rule20 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 Benign.

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	Not met	PVS1 is not applicable to this intronic variant (c.492+14dup). The PTEN PVS1 decision tree (VCEP v3.2.0) only covers nonsense, frameshift, canonical ±1,2 splice site disruptions, initiation codon variants, and single/multi-exon deletions. This variant is a deep intronic duplication that does not fall into any PVS1-qualifying variant class. SpliceAI predicts no significant splice impact (max delta 0.03).	spliceai cspec
PS1	N/A	PS1 applies to same amino acid change as known pathogenic variant or different nucleotide at same position as a known pathogenic splicing variant. This is an intronic duplication (c.492+14dup) with no known pathogenic variant at this intronic position.
PS2	Not assessed	No de novo observations of NM_000314.8:c.492+14dup have been identified in ClinVar, LOVD, or published literature. Without a confirmed de novo occurrence in a patient with PTEN hamartoma tumor syndrome and no family history, PS2 cannot be applied.
PS3	Not assessed	No RNA, mini-gene, or splicing functional assay data are available for c.492+14dup. The Mighell et al. 2018 (PMID:29706350) phosphatase activity assay (mmc2.xlsx) covers missense variants only and does not include this intronic variant. No functional evidence supports a damaging effect.
PS4	Not assessed	No proband counts, specificity scores, or case-control studies are available for this variant. The PTEN VCEP PS4 criteria require proband specificity scoring, which cannot be performed without individual-level phenotype data. ClinVar classifies this variant as Likely benign/Benign, suggesting no enrichment in affected individuals.	clinvar
PS5	N/A	PS5 is not a defined criterion in the ACMG/AMP 2015 framework or the PTEN VCEP v3.2.0 specifications. No such criterion exists for variant classification.
PM1	N/A	PM1 under PTEN VCEP applies only to variants located in catalytic motif residues (NP_000305.3: 90-94, 123-130, 166-168). c.492+14dup is an intronic variant that does not alter any amino acid residue and lies outside all catalytic domains.
PM2	Not met	The overall gnomAD frequency is very low (v4.1: 4/1,601,512, AF = 0.00025%), meeting the PTEN VCEP main threshold of <0.001%. However, the PTEN VCEP PM2 rule also requires that if multiple alleles are present in any subpopulation, the subpopulation AF must be <0.002% (0.00002). In gnomAD v4.1, the Middle Eastern subpopulation has 2 alleles out of 6,068 (AF = 0.033%), exceeding the 0.002% subpopulation threshold. Therefore PM2_Supporting is not met.	gnomad_v4
PM4	N/A	PM4 under PTEN VCEP applies to in-frame insertions/deletions impacting a catalytic motif residue or causing protein extension. c.492+14dup is an intronic duplication that does not alter protein length or affect any catalytic motif residue.
PM5	N/A	PM5 under PTEN VCEP applies to missense changes at a residue where a different pathogenic/likely pathogenic missense change has been observed. This is an intronic duplication, not a missense variant. pm5_candidates.json confirms no eligible comparators.
PM6	Not assessed	No assumed de novo observations of c.492+14dup have been reported in ClinVar, LOVD, or published literature. PM6 requires an assumed de novo occurrence in a proband with disease and no family history.
PP1	Not assessed	No co-segregation data are available for c.492+14dup. The PTEN VCEP requires at least 3-4 meioses for PP1_Supporting; no family studies involving this variant have been published.
PP2	N/A	PP2 under PTEN VCEP applies to missense variants in a gene with a low rate of benign missense variation. This is an intronic duplication, not a missense variant.
PP3	Not met	PP3 under PTEN VCEP requires SpliceAI scores of 0.5-1.0 for splicing variants (with VarSeak concordance). SpliceAI max delta score for c.492+14dup is 0.03, which is far below the 0.5 threshold. REVEL and BayesDel are not applicable (not SNV). No computational evidence supports a deleterious effect.	spliceai
PP4	N/A	PP4 is deemed Not Applicable by the PTEN VCEP v3.2.0. Phenotype specificity has been incorporated into the PS4 rule specifications.	cspec
PP5	N/A	PP5 is deemed Not Applicable for this VCEP by the PTEN Expert Panel v3.2.0. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	BA1 under PTEN VCEP requires gnomAD filtering allele frequency >0.056% (0.00056). The v4.1 grpmax filtering AF is 0.0058% (5.81e-05), which is an order of magnitude below the BA1 threshold.	gnomad_v4
BS1	Met	BS1_Strong under PTEN VCEP applies when gnomAD filtering allele frequency is 0.0043% to 0.056%. The gnomAD v4.1 grpmax filtering AF for c.492+14dup is 5.81e-05 (0.0058%), which falls within the BS1_Strong range (0.0043%-0.056%). This variant is observed at a population frequency higher than expected for a fully penetrant PTEN pathogenic variant causing PHTS.	gnomad_v4 cspec
BS2	Not met	BS2 under PTEN VCEP requires observation of the variant in the homozygous state in a healthy or PHTS-unaffected individual. This variant has zero homozygotes in gnomAD v2.1 (0/250,646) and v4.1 (0/1,601,512). No homozygous observations are documented.	gnomad_v2 gnomad_v4
BS3	Not assessed	BS3_Strong under PTEN VCEP for intronic variants requires RNA/mini-gene assay demonstrating no splicing impact. No such functional data are available for c.492+14dup. BS3_Supporting (phosphatase activity >0 per Mighell et al. 2018) applies only to missense variants. SpliceAI prediction of no impact (max delta 0.03) is computational, not functional evidence.	spliceai
BS4	Not assessed	No segregation data are available for c.492+14dup. BS4 under PTEN VCEP requires lack of segregation in affected family members; no such studies have been published for this variant.
BP1	N/A	BP1 is deemed Not Applicable by the PTEN VCEP v3.2.0. This rule (missense variant in gene where primarily truncating variants cause disease) is not applicable to PTEN.	cspec
BP2	Not assessed	No observations of c.492+14dup in trans with a pathogenic/likely pathogenic PTEN variant or in cis with multiple P/LP PTEN variants have been reported. Phased data are not available from population databases.
BP3	N/A	BP3 is deemed Not Applicable by the PTEN VCEP v3.2.0. This rule (in-frame deletions/insertions in repetitive regions) is not applicable to PTEN.	cspec
BP4	Not met	BP4 under PTEN VCEP requires concordance of SpliceAI and VarSeak predicting no splicing impact (SpliceAI 0-0.2, VarSeak Class 1-2). SpliceAI max delta score for c.492+14dup is 0.03, which falls within the 0-0.2 range. However, VarSeak data are not available, and the PTEN VCEP requires concordance of both tools. A single computational prediction is insufficient to meet BP4.	spliceai
BP5	Not assessed	BP5 under PTEN VCEP requires at least two cases where the variant is found with an alternate molecular basis for disease, with no phenotypic overlap. No such cases have been reported for c.492+14dup.
BP6	N/A	BP6 is deemed Not Applicable for this VCEP by the PTEN Expert Panel v3.2.0. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	Met	BP7 under PTEN VCEP applies to intronic variants at or beyond +7/-21 for which splicing prediction algorithms predict no impact. c.492+14dup is located at position +14 in intron 5 (beyond the +7 threshold). SpliceAI predicts no significant splice impact (max delta score 0.03), and the variant does not create a new splice site.	spliceai cspec

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