Variant classification summary

NM_000314.8:c.63C>T

PTEN · NP_000305.3:p.(Phe21=) · NM_000314.8

GRCh37: chr10:89624289 C>T · GRCh38: chr10:87864532 C>T

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.(Phe21=)

gnomAD AF

6.195249482696668e-07 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000314.8:c.63C>T is a synonymous substitution (NP_000305.3:p.Phe21=) in PTEN exon 1 that does not alter the encoded amino acid sequence.

2

SpliceAI predicts no significant splicing impact (max delta score 0.116), supporting BP7 at supporting strength for a synonymous variant located outside the splice consensus region.

3

The variant is essentially absent from population databases (gnomAD v4.1 allele frequency 6.2e-7, 1/1,614,140 alleles, 0 homozygotes), meeting PM2 at supporting strength.

4

ClinVar reports the variant as Likely benign (3 submitters) and Benign (1 submitter) under a single-submitter, non-expert-panel review status; PP5 and BP6 are not applicable under the PTEN VCEP.

5

With only PM2_Supporting and BP7 met and no strong or moderate criteria satisfied, the variant is classified as a Variant of Uncertain Significance.

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	NM_000314.8:c.63C>T is a synonymous substitution (p.Phe21=) and does not create a null allele (nonsense, frameshift, canonical splice, or initiation-codon variant), so the PTEN PVS1 decision tree does not apply.	pvs1_variant_assessment pvs1_gene_context
PS1	N/A	A synonymous change does not alter the amino acid, so there is no established pathogenic variant with the same amino acid change, and no established pathogenic splicing variant occurs at this nucleotide position.
PS2	Not met	No de novo (maternity and paternity confirmed) observation of this variant has been reported.
PS3	Not met	No RNA, mini-gene, or other splicing assay demonstrates a damaging effect, and the variant is synonymous and absent from the Mighell et al. missense saturation mutagenesis dataset (mmc2.xlsx covers missense variants only).	vcep_mmc2
PS4	Not met	No proband specificity score, case-control prevalence data, or variant-specific proband observations are available.
PS5	N/A	PS5 is not defined in the ClinGen PTEN VCEP framework and is not a standard ACMG/AMP criterion.
PM1	Not met	Residue 21 lies outside the PTEN catalytic motifs (WPD loop 90-94, P-loop 123-130, TI-loop 166-168), and the synonymous change does not alter these domains.	cspec
PM2	Met	The variant is essentially absent from population databases (gnomAD v4.1 allele frequency 6.2e-7; 1/1,614,140 alleles, 0 homozygotes), below the PTEN VCEP PM2_Supporting threshold of 0.001%.	gnomad_v4 gnomad_v2 gnomad_canada
PM5	N/A	The synonymous variant (p.Phe21=) is not a missense change at a residue with an established pathogenic missense comparator.	pm5_candidates
PM6	Not met	No assumed de novo observation of this variant has been reported.
PP1	Not met	No co-segregation data in affected family members are available.
PP2	N/A	PP2 applies to missense variants in a gene with a low rate of benign missense variation; this is a synonymous variant.	cspec
PP3	Not met	SpliceAI (max delta 0.116) predicts no splicing impact, and REVEL/BayesDel are not applicable to a synonymous variant; no concordant computational evidence of a deleterious effect is present.	spliceai
PP4	N/A	The ClinGen PTEN VCEP specifies PP4 as Not Applicable (phenotype specificity is incorporated into the PS4 rule specifications).	cspec
PP5	N/A	The ClinGen PTEN VCEP specifies PP5 as Not Applicable, and the ClinVar review status is single-submitter (not a 3-star expert panel).	cspec clinvar
BA1	Not met	gnomAD filtering allele frequency (6.2e-7) is far below the BA1 stand-alone threshold (>0.056%).	gnomad_v4
BS1	Not met	gnomAD allele frequency (6.2e-7) is below the BS1_Supporting threshold (>=0.00043%).	gnomad_v4
BS2	Not met	No homozygous observation in healthy or PHTS-unaffected individuals (gnomAD homozygote count = 0).	gnomad_v4
BS3	Not met	No RNA, mini-gene, or other splicing assay demonstrates absence of splicing impact; computational prediction alone does not satisfy BS3.
BS4	Not met	No family data demonstrate lack of segregation with disease.
BP1	N/A	The ClinGen PTEN VCEP specifies BP1 as Not Applicable (PTEN disease is not primarily caused by truncating variants).	cspec
BP2	Not met	No observation in trans with a pathogenic/likely pathogenic PTEN variant, nor three observations in cis or phase-unknown with different pathogenic/likely pathogenic PTEN variants.
BP4	Not met	SpliceAI (max delta 0.116) is within the benign range (0-0.2), but the PTEN VCEP BP4 rule requires concordance of SpliceAI AND VarSeak; VarSeak data are unavailable. BP7 is applied instead to avoid double-counting.	spliceai cspec
BP5	Not met	No case with an alternate molecular basis for disease has been reported.
BP6	N/A	The ClinGen PTEN VCEP specifies BP6 as Not Applicable, and the ClinVar review status is single-submitter (not a 3-star expert panel).	cspec clinvar
BP7	Met	Synonymous variant located outside the splice consensus region (c.63 in exon 1, 16 bp upstream of the exon 1 donor) with SpliceAI predicting no impact on splicing (max delta 0.116), meeting BP7 at supporting level.	spliceai cspec
BP3	N/A	In-frame indel / repeat-region criterion; not applicable to a single-nucleotide substitution.
PM3	N/A	Recessive trans-phase criterion; PTEN is autosomal dominant and PM3 is Not Applicable per the VCEP.	cspec
PM4	N/A	Protein-length-change (in-frame indel / stop-loss) criterion; not applicable to a synonymous substitution.

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