NM_000314.8:c.-307C>G

PTEN · NP_000305.3:p.? · NM_000314.8

GRCh37: chr10:89623920 C>G · GRCh38: chr10:87864163 C>G

Gene: PTEN Transcript: NM_000314.8

Final call

Likely Benign

BS1 strong

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

The PTEN c.-307C>G (NP_000305.3:p.?) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.

This variant is absent from gnomAD v2.1, but in gnomAD v4.1 it is present at an overall allele frequency of 5.31e-06 and reaches 1.23e-04 in the Ashkenazi Jewish population, which meets the PTEN BS1 strong frequency range and is above the PTEN PM2 subpopulation threshold.

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00, and no PTEN-specific computational evidence supporting a deleterious effect was identified.

Final determination: Rule20 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 Likely Benign.

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	This variant is an upstream noncoding substitution and does not fall into the PTEN PVS1 decision tree categories for nonsense, frameshift, canonical +/-1,2 splice-site, or qualifying exon-level loss-of-function variants. Available evidence does not support applying PVS1 to this promoter-region change.	cspec pvs1_gene_context pvs1_variant_assessment vcep_pvs1_decisiontree_pten
PS1	N/A	This criterion is not applicable because the variant does not define an amino acid change, and no same-nucleotide pathogenic splicing comparator was identified for this upstream substitution.	cspec
PS2	Not assessed	No confirmed de novo occurrence was identified for this variant, so PS2 cannot be assessed from the available evidence.	clinvar
PS3	Not assessed	No well-established functional study was identified showing that this exact upstream variant damages PTEN function or splicing. The PTEN phosphatase saturation assay is specified for missense variants and does not address this promoter-region substitution.	cspec vcep_mmc2
PS4	Not assessed	No affected-proband series, enrichment data, or case-control evidence was identified for this exact variant, so PS4 is not established.	clinvar cspec
PM1	N/A	This criterion is not applicable because the PTEN PM1 specification is defined for established protein catalytic motifs, and this upstream noncoding variant is outside those residues.	cspec
PM2	Not met	Population frequency does not meet the PTEN PM2_Supporting threshold. Although the overall gnomAD v4.1 allele frequency is 5.31e-06, below the <1.0e-05 threshold, the highest observed subpopulation frequency is 1.23e-04 in Ashkenazi Jewish individuals with 2 alleles, which is above the required <2.0e-05 subpopulation threshold when multiple alleles are present.	gnomad_v4 gnomad_v2 cspec
PM3	N/A	This criterion is not applicable in the PTEN specification.	cspec
PM4	N/A	This upstream substitution does not cause a protein length change, in-frame insertion/deletion, or stop-loss event, so PM4 is not applicable.	cspec
PM5	N/A	This criterion is not applicable because the PTEN PM5 rule uses classic same-residue missense logic, and this variant is not missense-like.	pm5_candidates cspec
PM6	Not assessed	No presumed de novo observation was identified for this variant, so PM6 cannot be applied.	clinvar cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be assessed.	clinvar cspec
PP2	N/A	This criterion is not applicable because PP2 is a missense-based rule and this variant does not produce a missense change.	cspec
PP3	Not met	Available computational evidence does not support a deleterious splicing effect under the PTEN PP3 rule. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and this upstream noncoding variant has no REVEL score because it is not missense.	spliceai cspec
PP4	N/A	This criterion is not applicable in the PTEN specification because phenotype specificity is incorporated into PS4.	cspec
PP5	N/A	This criterion is not applicable in the PTEN specification.	cspec
BA1	Not met	Population frequency does not reach the PTEN BA1 threshold. The highest observed gnomAD v4.1 subpopulation allele frequency is 1.23e-04, which is below the BA1 cutoff of >5.6e-04.	gnomad_v4 cspec
BS1	Met	Population frequency meets the PTEN BS1 strong threshold. The highest observed gnomAD v4.1 subpopulation allele frequency is 1.23e-04 in Ashkenazi Jewish individuals, which falls within the PTEN BS1 strong range of 4.3e-05 to 5.6e-04.	gnomad_v4 cspec
BS2	Not met	Available population data do not support BS2 because no homozygous individuals were reported in gnomAD for this variant.	gnomad_v4 cspec
BS3	Not assessed	No functional study was identified showing that this exact upstream variant has no damaging effect on PTEN function or splicing, so BS3 cannot be applied.	cspec vcep_mmc2
BS4	Not assessed	No lack-of-segregation evidence was identified for this variant, so BS4 cannot be assessed.	clinvar cspec
BP1	N/A	This criterion is not applicable in the PTEN specification.	cspec
BP2	Not assessed	No phase data were identified showing this variant in trans with a pathogenic PTEN variant or repeatedly in cis/phase unknown with different pathogenic PTEN variants, so BP2 cannot be assessed.	clinvar cspec
BP3	N/A	This criterion is not applicable in the PTEN specification.	cspec
BP4	Not met	Available computational evidence does not satisfy the PTEN BP4 rule for a benign prediction. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, but the PTEN BP4 specification requires concordant splicing predictions for qualifying splicing-region variants or REVEL <0.5 for missense variants, and this upstream noncoding substitution is neither.	spliceai cspec
BP5	Not assessed	No alternate highly penetrant molecular diagnosis with a non-overlapping phenotype was identified, so BP5 cannot be assessed.	clinvar cspec
BP6	N/A	This criterion is not applicable in the PTEN specification.	cspec
BP7	N/A	This criterion is not applicable because the variant is not a synonymous variant and is not an intronic variant at or beyond +7/-21.	cspec spliceai

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.