Variant classification summary

NM_000314.8:c.388_389insA

PTEN · NP_000305.3:p.(Arg130GlnfsTer50) · NM_000314.8

GRCh37: chr10:89692904 C>CA · GRCh38: chr10:87933147 C>CA

Gene: PTEN Transcript: NM_000314.8

Final call

Pathogenic

PVS1 very strong PM1 moderate PM2 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Arg130GlnfsTer50)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000314.8:c.388_389insA is a frameshift insertion in PTEN exon 5 producing p.Arg130GlnfsTer50, predicted to undergo nonsense-mediated decay well 5' of the p.D375 threshold, meeting PVS1 (very strong) per the ClinGen PTEN Expert Panel PVS1 decision tree v3.2.0.

2

The variant disrupts codon 130 within the PTEN catalytic motif (residues 123-130, NP_000305.3), a critical functional domain, meeting PM1 (moderate) per PTEN VCEP specifications.

3

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting level per PTEN VCEP allele frequency threshold of <0.00001 (0.001%).

4

No functional studies, case reports, de novo observations, or segregation data were identified for this variant in the reviewed literature.

5

Under the PTEN VCEP classification framework, PVS1 (very strong) plus one moderate criterion (PM1) meets Rule 10 for Likely Pathogenic classification.

Final determination: Rule3 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 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	Frameshift insertion c.388_389insA produces a premature termination codon at p.Arg130GlnfsTer50 (p.179), which is 5' of the p.D375 (c.1121) threshold in the PTEN VCEP PVS1 decision tree. The variant is predicted to undergo nonsense-mediated decay. Assigned PVS1 (very strong) per ClinGen PTEN Expert Panel specifications v3.2.0.	vcep_pvs1_decisiontree_pten pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 applies to variants producing the same amino acid change as a known pathogenic variant. This is a frameshift insertion producing a novel reading frame with a premature termination codon; there is no applicable 'same amino acid change' comparator for a frameshift variant.
PS2	Not met	No de novo observation with confirmed paternity and maternity has been identified for this variant in the available evidence.
PS3	Not met	No variant-specific functional assay data is available for NM_000314.8:c.388_389insA. The PTEN VCEP-designated Mighell et al. 2018 (PMID: 29706350) saturation mutagenesis assay (mmc2.xlsx) covers missense variants only and does not include frameshift variants. The two reviewed publications (PMID: 11237521, PMID: 17218262) discuss PTEN at the gene level and do not report functional data for this variant.
PS4	Not met	No proband counts or case-control data are available for this variant. The variant is absent from ClinVar, and no case reports mentioning this variant were identified in the reviewed literature.
PS5	N/A	PS5 is not a recognized ACMG/AMP criterion. The ACMG/AMP 2015 framework does not include PS5.
PM1	Met	The variant disrupts codon 130 (p.Arg130), which lies within the PTEN VCEP-defined catalytic motif spanning residues 123-130 (NP_000305.3). This frameshift insertion removes the critical phosphatase catalytic domain function. Additionally, the residue lies within a statistically significant cancer hotspot (cancerhotspots.org).	cspec
PM2	Met	This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, satisfying the PTEN VCEP PM2 threshold of allele frequency <0.00001 (0.001%). Per VCEP specification, PM2 is applied at supporting evidence level.	gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	The PTEN VCEP PM4 specification applies to in-frame insertions/deletions impacting catalytic motif residues and to stop-loss variants causing protein extension. This variant is a frameshift insertion, not an in-frame indel, and is appropriately addressed under PVS1 rather than PM4.
PM5	N/A	PM5 requires a missense change at an amino acid residue where a different pathogenic missense change has been seen. This variant is a frameshift insertion, not a missense substitution, and does not meet the residue-level missense comparator requirement.
PM6	Not met	No assumed de novo observation has been reported for this variant. No proband with disease and no family history is documented in the available evidence.
PP1	Not met	No co-segregation data are available for this variant. No families with multiple affected members have been reported.
PP2	N/A	PP2 is specified for missense variants in genes with a low rate of benign missense variation. This variant is a frameshift insertion, not a missense substitution.
PP3	N/A	The PTEN VCEP PP3 specification applies REVEL score >0.7 for missense variants, or SpliceAI/VarSeak concordance for splicing variants. This is a frameshift insertion; REVEL and BayesDel scores are not available for insertion variants, and SpliceAI predicts no splice impact (max delta 0.01). No applicable in silico evidence can be assessed.
PP4	N/A	The PTEN VCEP considers PP4 not applicable; phenotype specificity has been incorporated into the PS4 rule specifications.	cspec
PP5	N/A	The PTEN VCEP designates PP5 as not applicable per ClinGen SVI VCEP Review Committee recommendations.	cspec
BA1	Not met	The variant is absent from gnomAD (allele frequency 0). The PTEN VCEP BA1 threshold of >0.00056 (0.056%) filtering allele frequency is not met.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD. The PTEN VCEP BS1 thresholds (0.000043-0.00056 for strong, 0.0000043-0.000043 for supporting) are not met at zero allele frequency.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous observation in a healthy or PHTS-unaffected individual has been reported for this variant. The variant is absent from gnomAD, and no clinical data support a homozygous healthy carrier.
BS3	Not met	No well-established functional studies demonstrate a benign effect for this variant. The PTEN VCEP BS3 specifications apply to splicing assays (strong) or Mighell et al. 2018 phosphatase activity >0 (supporting), which is limited to missense variants and does not address this frameshift insertion.
BS4	Not met	No lack-of-segregation data are available for this variant. No families with affected members lacking the variant have been reported.
BP1	N/A	The PTEN VCEP designates BP1 as not applicable to PTEN.	cspec
BP2	Not met	No observation of this variant in trans with a pathogenic or likely pathogenic PTEN variant, and no observations in cis with different P/LP PTEN variants have been reported.
BP3	N/A	BP3 is designated as not applicable by the PTEN VCEP.	cspec
BP4	N/A	The PTEN VCEP BP4 applies to synonymous or intronic variants with concordant benign SpliceAI/VarSeak predictions, or missense variants with REVEL <0.5. This is a frameshift insertion; BP4 is not specified for frameshift variants, and the SpliceAI max delta of 0.01 is not informative for a coding frameshift.
BP5	Not met	No observation of this variant in a case with an alternate molecular basis for disease has been reported. The PTEN VCEP requires at least two such cases.
BP6	N/A	The PTEN VCEP designates BP6 as not applicable per ClinGen SVI VCEP Review Committee recommendations.	cspec
BP7	N/A	BP7 applies to synonymous or intronic variants at or beyond +7/-21 with no predicted splice impact. This is a coding frameshift insertion and does not meet the variant type requirement.

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