Variant classification summary

NM_000314.8:c.348del

PTEN · NP_000305.3:p.(Asp116GlufsTer18) · NM_000314.8

GRCh37: chr10:89692863 AC>A · GRCh38: chr10:87933106 AC>A

Gene: PTEN Transcript: NM_000314.8

Final call

VUS

PVS1 PM2_Supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Asp116GlufsTer18)

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000314.8:c.348del predicts PTEN p.(Asp116GlufsTer18), a frameshift expected to truncate the protein early in exon 5.

2

The PTEN PVS1 decision tree assigns PVS1 to frameshift variants in NM_000314.8 when the stop/disruption occurs at or 5' to p.D375 (c.1121); this variant truncates at p.Asp116fs, which is well upstream of that threshold and is consistent with loss of function.

3

The variant is absent from gnomAD v2.1 and gnomAD v4.1, and the PTEN specification applies PM2 at Supporting strength for variants with allele frequency below 0.00001, with a subpopulation threshold below 0.00002 when multiple alleles are present.

4

No PTEN-specific final classification framework was retrieved, so the generic ACMG/AMP combination rules were used as fallback; with PVS1 and PM2_Supporting alone, this evidence set does not reach a defined pathogenic or likely pathogenic combination under those rules, and the variant is therefore classified as a variant of uncertain significance pending human review.

Final determination:

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.348del is a frameshift variant predicted to cause p.(Asp116GlufsTer18). The PTEN-specific PVS1 decision tree assigns PVS1 to frameshift variants in biologically relevant transcript NM_000314.8 when the stop/disruption is at or 5' to p.D375 (c.1121); p.Asp116fs is well upstream of this threshold and is predicted to undergo NMD.	vcep_p_v_s_1___d_e_c_i_s_i_o_n_t_r_e_e___p_t_e_n cspec
PS1	N/A	PS1 is specified for the same amino acid substitution as a known pathogenic variant or equivalent splicing effect. This variant is a frameshift, not a single amino acid substitution.	cspec
PS2	Not assessed	No de novo case data with confirmed maternity and paternity were provided.	cspec
PS3	N/A	No RNA or splicing assay evidence was provided for this deletion, and the PTEN functional dataset indexed for PS3/BS3 is a missense phosphatase assay that does not apply to this frameshift variant.	cspec vcep_m_m_c_2
PS4	Not assessed	No germline proband counts or PTEN phenotype specificity scoring data were provided to compare case prevalence with controls under the PTEN specification.	cspec
PM1	Not met	The PTEN PM1 specification is limited to catalytic motif residues 90-94, 123-130, and 166-168. This variant affects codon 116, which is outside those defined PM1 residues, and no statistically significant hotspot evidence was provided.	cspec
PM2	Met	The variant is absent from gnomAD v2.1 and gnomAD v4.1. Under the PTEN specification, PM2 is applied at Supporting strength when allele frequency is <0.00001 (0.001%) and, if multiple alleles are present in a subpopulation, the subpopulation frequency is <0.00002 (0.002%); absence from both datasets satisfies this rule.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable for the PTEN VCEP.	cspec
PM4	N/A	PM4 is specified for in-frame insertions/deletions affecting defined motifs or for stop-loss variants. This variant is a frameshift loss-of-function variant, so PM4 does not apply.	cspec
PM5	N/A	PM5 is a missense criterion and does not apply to this frameshift variant.	cspec
PM6	Not assessed	No assumed de novo observations in affected individuals without family history were provided.	cspec
PP1	Not assessed	No segregation data were provided to count informative meioses.	cspec
PP2	N/A	PP2 is a missense criterion and does not apply to this frameshift variant.	cspec
PP3	N/A	PTEN PP3 is specified for missense variants using REVEL or for splicing variants with concordant splice predictors. This exonic frameshift deletion is not a missense variant, is not a splice-region variant, and no concordant splicing framework beyond SpliceAI was provided.	cspec spliceai
PP4	N/A	PP4 is not applicable for the PTEN VCEP because phenotype specificity has been incorporated into PS4.	cspec
BA1	Not met	The variant is absent from gnomAD v2.1 and v4.1, so it does not exceed the PTEN BA1 filtering allele frequency threshold of >0.00056 (0.056%).	cspec gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD v2.1 and v4.1, so it does not fall within the PTEN BS1 frequency ranges of 0.000043-0.00056 for Strong or 0.0000043-0.000043 for Supporting evidence.	cspec gnomad_v2 gnomad_v4
BS2	Not met	No observation of this variant in the homozygous state in a healthy or PTEN-hamartoma-tumor-syndrome-unaffected individual was provided.	cspec
BS3	N/A	No functional study showing no damaging effect was provided for this frameshift variant, and the indexed PTEN functional assay file is a missense phosphatase dataset that does not apply here.	cspec vcep_m_m_c_2
BS4	Not assessed	No family data demonstrating lack of segregation were provided.	cspec
BP1	N/A	BP1 is not applicable for the PTEN VCEP.	cspec
BP2	Not assessed	No phase data were provided showing this variant in trans with a pathogenic PTEN variant or in cis/phase unknown on at least three occasions with different pathogenic PTEN variants.	cspec
BP3	N/A	BP3 is not applicable for the PTEN VCEP.	cspec
BP4	N/A	PTEN BP4 is specified for synonymous or intronic variants with benign splicing predictions, or missense variants with REVEL <0.5. This variant is an exonic frameshift deletion, so BP4 does not apply.	cspec spliceai
BP5	Not assessed	No evidence was provided for at least two cases with an alternate highly penetrant molecular diagnosis and a nonoverlapping phenotype.	cspec
BP6	N/A	BP6 is not for use in this VCEP.	cspec
BP7	N/A	BP7 is limited to synonymous or deep intronic variants without predicted splice impact and does not apply to this frameshift deletion.	cspec
PP5	N/A	PP5 is not for use in this VCEP.	cspec

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