Variant classification summary

NM_000314.8:c.387_388del

PTEN · NP_000305.3:p.(Arg130AsnfsTer49) · NM_000314.8

GRCh37: chr10:89692902 GAC>G · GRCh38: chr10:87933145 GAC>G

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.(Arg130AsnfsTer49)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (very strong): NM_000314.8:c.387_388del is a frameshift deletion in exon 5 producing p.(Arg130AsnfsTer49) with a premature termination codon at position 178, well 5' of the PTEN VCEP p.D375 (c.1121) threshold. The variant is predicted to undergo NMD in the biologically-relevant transcript NM_000314.8.

2

PM1 (moderate): The variant disrupts residue R130, which lies within the PTEN catalytic motif (residues 123-130, NP_000305.3) as defined by the VCEP. This residue is also identified as a statistically significant hotspot by cancerhotspots.org.

3

PM2 (supporting): The variant is absent from all gnomAD population databases (v2.1, v4.1, Canada v1.0), meeting the VCEP threshold for PM2_Supporting (allele frequency < 0.001%).

4

Under the PTEN VCEP v3.2 classification rules (Rule 10): PVS1 (very strong) + 1 moderate criterion (PM1) = Likely Pathogenic. PM2 (supporting) provides additional supportive evidence.

Final determination: Rule3 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.387_388del is a frameshift deletion in exon 5 producing a premature termination codon at NP_000305.3:p.(Arg130AsnfsTer49). Under the PTEN VCEP PVS1 decision tree, frameshift variants predicted to undergo NMD with a stop codon at or 5' of p.D375 (c.1121) in the biologically-relevant transcript NM_000314.8 are assigned PVS1 at very strong strength. The variant occurs at c.387, well before the c.1121 threshold, and exon 5 is present in NM_000314.8.	vcep_pvs1_decisiontree_pten cspec
PS1	Not met	PS1 under the PTEN VCEP requires either the same amino acid change as a previously established pathogenic variant, or a different variant at the same nucleotide position as a known pathogenic splicing variant. NM_000314.8:c.387_388del is a frameshift deletion producing p.Arg130AsnfsTer49. No previously established pathogenic variant shares this same amino acid change, and there is no known pathogenic splicing variant at nucleotide position c.387 or c.388.	cspec
PS2	Not met	PS2 under the PTEN VCEP requires a de novo observation (maternity and paternity confirmed) in a patient with disease and no family history. No de novo data are available for NM_000314.8:c.387_388del in ClinVar or the reviewed literature.	cspec
PS3	Not met	PS3 under the PTEN VCEP may be applied based on RNA/mini-gene splicing assays (strong), phosphatase activity ≤ -1.11 per Mighell et al. 2018 (moderate, missense only), or phosphatase activity <50% of wild-type (supporting). NM_000314.8:c.387_388del is a frameshift deletion, not a missense variant, so the Mighell et al. saturation mutagenesis data (mmc2.xlsx) does not apply. No variant-specific functional studies were identified in the reviewed literature.	cspec vcep_mmc2
PS4	Not met	PS4 under the PTEN VCEP requires probands with a specificity score or significantly increased prevalence in affected individuals. The variant is absent from ClinVar with no submitted classifications, and no proband data or case-control studies are available.	cspec clinvar
PS5	N/A	PS5 is not a criterion in the ClinGen PTEN VCEP v3.2 framework; the VCEP's PS1 rule covers same amino acid change evidence.	cspec
PM1	Met	Under the PTEN VCEP, PM1 applies at moderate strength when a variant is located in a mutational hotspot and/or critical functional domain. The catalytic motifs are defined as residues 90-94, 123-130, and 166-168 (NP_000305.3). NM_000314.8:c.387_388del produces p.Arg130AsnfsTer49, disrupting the 123-130 catalytic motif at residue R130. Additionally, cancerhotspots.org identifies this position as a statistically significant hotspot.	cspec
PM2	Met	Under the PTEN VCEP, PM2 applies at supporting strength when a variant is absent from gnomAD or present at <0.00001 (0.001%) allele frequency. NM_000314.8:c.387_388del is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM4	N/A	Under the PTEN VCEP, PM4 applies only to in-frame insertions or deletions impacting a catalytic motif residue, or variants causing protein extension. NM_000314.8:c.387_388del is an out-of-frame (frameshift) deletion, not an in-frame deletion, and is captured by PVS1 instead.	cspec
PM5	N/A	Under the PTEN VCEP, PM5 applies to missense changes at an amino acid residue where a different missense change has been determined to be pathogenic or likely pathogenic. NM_000314.8:c.387_388del is a frameshift deletion, not a missense variant. The pm5_candidates analysis confirmed no eligible missense comparators.	cspec pm5_candidates
PM6	Not met	PM6 under the PTEN VCEP requires assumed or confirmed de novo observations in a proband with disease and no family history. No de novo data are available for NM_000314.8:c.387_388del.	cspec
PP1	Not met	PP1 under the PTEN VCEP requires co-segregation data with at least 3 meioses. No segregation data are available for NM_000314.8:c.387_388del.	cspec
PP2	N/A	Under the PTEN VCEP, PP2 applies to missense variants in a gene with a low rate of benign missense variation. NM_000314.8:c.387_388del is a frameshift deletion, not a missense variant.	cspec
PP3	Not met	Under the PTEN VCEP, PP3 applies to missense variants with REVEL > 0.7 or splicing variants with concordant SpliceAI and VarSeak predictions. NM_000314.8:c.387_388del is a frameshift deletion with no REVEL score, and SpliceAI predicts no significant splice impact (max delta = 0.01).	cspec spliceai
PP4	N/A	The PTEN VCEP designates PP4 as Not Applicable; phenotype specificity has been incorporated into PS4 rule specifications.	cspec
PP5	N/A	The PTEN VCEP designates PP5 as Not Applicable for this VCEP, per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BA1	Not met	BA1 under the PTEN VCEP requires a gnomAD filtering allele frequency >0.00056 (0.056%). NM_000314.8:c.387_388del is absent from all gnomAD populations.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS1	Not met	BS1 under the PTEN VCEP requires a gnomAD filtering allele frequency between 0.000043 (0.0043%) and 0.00056 (0.056%) for strong, or 0.0000043 (0.00043%) to 0.000043 (0.0043%) for supporting. NM_000314.8:c.387_388del is absent from all gnomAD populations.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS2	Not met	BS2 under the PTEN VCEP requires observation in the homozygous state in a healthy or PHTS-unaffected individual. No homozygous observations are reported for this variant.	cspec gnomad_v2 gnomad_v4
BS3	Not met	BS3 under the PTEN VCEP applies to splicing assays showing no impact (strong) or phosphatase activity >0 per Mighell et al. 2018 (supporting, missense only). NM_000314.8:c.387_388del is a frameshift deletion and is not eligible for the Mighell missense assay. No variant-specific benign functional data are available.	cspec vcep_mmc2
BS4	Not met	BS4 under the PTEN VCEP requires lack of segregation in affected members of one or more families. No segregation data are available for NM_000314.8:c.387_388del.	cspec
BP1	N/A	The PTEN VCEP designates BP1 as Not Applicable.	cspec
BP2	Not met	BP2 under the PTEN VCEP requires observation in trans with a pathogenic/likely pathogenic PTEN variant or at least three observations in cis/unknown phase with different pathogenic/likely pathogenic PTEN variants. No such observations exist for NM_000314.8:c.387_388del.	cspec
BP3	N/A	The PTEN VCEP designates BP3 as Not Applicable.	cspec
BP4	N/A	Under the PTEN VCEP, BP4 applies to synonymous or intronic variants where SpliceAI and VarSeak predict no splicing impact, or missense variants with REVEL < 0.5. NM_000314.8:c.387_388del is a frameshift deletion and does not fall under the VCEP's BP4 applicability criteria.	cspec spliceai
BP5	Not met	BP5 under the PTEN VCEP requires at least two cases where the variant is found in individuals with an alternate molecular basis for disease, where the other gene/disorder is highly penetrant and there is no phenotypic overlap. No such cases have been reported for NM_000314.8:c.387_388del.	cspec
BP6	N/A	The PTEN VCEP designates BP6 as Not Applicable for this VCEP, per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BP7	N/A	Under the PTEN VCEP, BP7 applies to synonymous (silent) or intronic variants at or beyond +7/-21 with no predicted splice impact. NM_000314.8:c.387_388del is a coding frameshift deletion, not a synonymous or intronic variant.	cspec

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