NM_000314.8:c.-361C>T

PTEN · NP_000305.3:p.? · NM_000314.8

GRCh37: chr10:89623866 C>T · GRCh38: chr10:87864109 C>T

Gene: PTEN Transcript: NM_000314.8

Final call

VUS

BS1 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.?

gnomAD AF

1.2192742879438159e-05 (v4.1)

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

The PTEN NM_000314.8:c.-361C>T (NP_000305.3:p.?) variant has not been reported in ClinVar.

This variant is absent from gnomAD v2.1 but present in gnomAD v4.1 at 6/492096 alleles, with filtering allele frequency 6.24e-06; this is above the PTEN PM2 cutoff and within the PTEN BS1_supporting frequency range.

Final determination: No criteria-combination rule matched the adjudicated criteria in the Richards et.al., 2015 - Combining rules v3.2.0 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	Not met	This 5'UTR variant does not fall into the PTEN PVS1 decision tree categories for nonsense, frameshift, canonical +/-1,2 splice, or exon-level loss-of-function variants, so PVS1 is not met.	cspec pvs1_gene_context pvs1_variant_assessment vcep_pvs1_decisiontree_pten
PS1	Not assessed	No previously established pathogenic variant causing the same amino acid change or an equivalent pathogenic splicing effect at this nucleotide was identified, so PS1 was not assessed.	cspec clinvar
PS2	Not assessed	No confirmed de novo occurrence in an affected individual was identified, so PS2 was not assessed.	cspec clinvar
PS3	Not assessed	No well-established functional study showing a damaging effect of this exact 5'UTR variant on PTEN splicing, transcript abundance, or gene function was identified, so PS3 was not assessed.	cspec vcep_mmc2
PS4	Not assessed	No enrichment data or counted affected probands meeting PTEN VCEP PS4 specifications were identified for this variant, so PS4 was not assessed.	cspec clinvar
PM1	N/A	This variant is in the 5'UTR and not in the PTEN catalytic motifs at residues 90-94, 123-130, or 166-168, so PM1 is not applicable.	cspec
PM2	Not met	This variant is absent from gnomAD v2.1 but is present in gnomAD v4.1 at AF 1.21927e-05, with highest subpopulation AF 4.45315e-05, which is above the PTEN PM2 threshold of <0.00001 overall and <0.00002 within a subpopulation when multiple alleles are observed; therefore PM2 is not met.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in the PTEN VCEP framework.	cspec
PM4	N/A	This variant does not cause an in-frame protein length change or stop-loss effect, so PM4 is not applicable.	cspec
PM5	N/A	PTEN uses classic same-residue missense PM5 logic, and this variant is not missense-like, so PM5 is not applicable.	cspec pm5_candidates
PM6	Not assessed	No presumed de novo occurrence without parental confirmation was identified, so PM6 was not assessed.	cspec clinvar
PP1	Not assessed	No segregation data were identified for this variant, so PP1 was not assessed.	cspec clinvar
PP2	N/A	PP2 is a missense criterion, and this variant is a 5'UTR substitution, so PP2 is not applicable.	cspec
PP3	Not assessed	The PTEN VCEP applies PP3 to concordant SpliceAI and VarSeak splicing predictions for synonymous or intronic variants, or to missense variants with REVEL >0.7. This 5'UTR variant is not missense, REVEL is unavailable, and no concordant PTEN VCEP splicing prediction result was available, so PP3 was not assessed.	cspec spliceai
PP4	N/A	PP4 is not applicable in the PTEN VCEP framework because phenotype specificity is incorporated into PS4.	cspec
PP5	N/A	PP5 is not applicable in the PTEN VCEP framework.	cspec
BA1	Not met	The gnomAD v4.1 filtering allele frequency for this variant is 6.24e-06, which is below the PTEN BA1 threshold of >0.00056, so BA1 is not met.	cspec gnomad_v4
BS1	Met	The gnomAD v4.1 filtering allele frequency is 6.24e-06, which falls within the PTEN BS1_Supporting range of 0.0000043 to 0.000043 and below the BS1 strong range of 0.000043 to 0.00056; therefore BS1 is met at supporting strength.	cspec gnomad_v4
BS2	Not met	No homozygous observation in a healthy or PTEN hamartoma tumor syndrome-unaffected individual was identified, so BS2 is not met.	cspec gnomad_v4
BS3	Not assessed	No well-established study showing no damaging effect of this exact 5'UTR variant on PTEN function or splicing was identified, so BS3 was not assessed.	cspec vcep_mmc2
BS4	Not assessed	No lack-of-segregation evidence was identified for this variant, so BS4 was not assessed.	cspec clinvar
BP1	N/A	BP1 is not applicable in the PTEN VCEP framework.	cspec
BP2	Not assessed	No observation of this variant in trans with a pathogenic PTEN variant, or at least three cis/phase-unknown observations with different pathogenic PTEN variants, was identified, so BP2 was not assessed.	cspec clinvar
BP3	N/A	BP3 is not applicable in the PTEN VCEP framework.	cspec
BP4	Not assessed	The PTEN VCEP applies BP4 to synonymous or intronic variants with concordant benign SpliceAI and VarSeak splicing predictions, or to missense variants with REVEL <0.5. This 5'UTR variant is not missense, REVEL is unavailable, and no concordant PTEN VCEP splicing prediction result was available, so BP4 was not assessed.	cspec spliceai
BP5	Not assessed	No alternate molecular diagnosis with non-overlapping phenotype was identified, so BP5 was not assessed.	cspec
BP6	N/A	BP6 is not applicable in the PTEN VCEP framework.	cspec
BP7	N/A	BP7 applies to synonymous or qualifying intronic variants, and this variant is a 5'UTR substitution, so BP7 is not applicable.	cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.