NM_000314.8:c.-638C>T

PTEN · NP_000305.3:p.? · NM_000314.8

GRCh37: chr10:89623589 C>T · GRCh38: chr10:87863832 C>T

Gene: PTEN Transcript: NM_000314.8

Final call

VUS

PM2 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.?

gnomAD AF

2.6136547780222995e-06 (v4.1)

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 supporting: the variant's gnomAD v4.1 allele frequency is below the PTEN VCEP rarity threshold.

Final determination: Under the PTEN Expert Panel Version 3.2 criteria-combination framework, PM2 supporting alone does not satisfy a pathogenic, likely pathogenic, benign, or likely benign rule, so the classification remains VUS.

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	Not applicable: c.-638C>T is a 5′-UTR variant with p.? and is outside the PTEN VCEP PVS1 decision tree’s null-variant categories.	cspec vcep_pvs1_decisiontree_pten
PS1	N/A	Not applicable: NM_000314.8:c.-638C>T has protein consequence p.? and does not produce an amino-acid change required for PS1.	cspec
PS2	Not assessed	Not assessed: no proband phenotype, parental testing, or documented de novo observation is available.	cspec
PS3	N/A	Not applicable: the variant is upstream of the PTEN coding sequence (p.=) and the governing functional assay rule covers missense substitutions only.	cspec vcep_mmc2
PS4	Not assessed	Not assessed: no proband specificity score or case-control result is available to compare with the PTEN PS4 thresholds (score ≥1 or odds ratio >2 with required statistical support).	cspec
PM1	N/A	Not applicable: the variant has no protein residue (p.?), so it cannot be evaluated against PTEN catalytic motifs 90-94, 123-130, or 166-168.	cspec
PM2	Met	Met at Supporting: gnomAD v4.1 total AF 2.6136547780222995e-06 is below the PTEN PM2 threshold <0.00001.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the PTEN VCEP Version 3.2 specification explicitly marks PM3 as not applicable for PTEN.	cspec
PM4	N/A	Not applicable: the 5′-UTR c.-638C>T substitution has p.? and no evidence of an in-frame indel, stop-loss, extension, or protein-length change.	cspec
PM5	N/A	Not applicable: NM_000314.8:c.-638C>T is noncoding with protein consequence p.? and is not a missense change at an amino-acid residue.	cspec
PM6	Not assessed	Not assessed: no presumed or proven de novo observation, affected proband, or parental testing is documented.	cspec
PP1	Not assessed	Not assessed: no affected relatives, segregation results, or meioses are documented against the 3-meiosis minimum.	cspec
PP2	N/A	Not applicable: the upstream variant has protein consequence p.? and does not meet PP2's required missense-variant criterion.	cspec
PP3	N/A	Not applicable: c.-638C>T is a 5' untranslated-region variant, outside the PTEN VCEP PP3 scope for missense or splice-region/intronic variants.	cspec
PP4	N/A	Not applicable: the PTEN VCEP explicitly excludes PP4 and incorporates phenotype specificity into PS4 Use 2 instead.	cspec
PP5	N/A	Not applicable: the PTEN VCEP excludes PP5, and the exact variant has no ClinVar record or Expert Panel pathogenic classification.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 total AF is 2.6136547780222995e-06 versus the PTEN BA1 filtering-AF threshold >0.00056.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 total AF is 2.6136547780222995e-06, below the PTEN BS1 Supporting lower threshold 0.0000043.	cspec gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD v4.1 and gnomAD v3.1 non-cancer each report 0 homozygotes for the variant.	cspec gnomad_v4
BS3	N/A	Not applicable: the upstream variant has protein consequence p.=, whereas the governing BS3 assay evidence is restricted to functional protein variants.	cspec vcep_mmc2
BS4	Not assessed	Not assessed: no affected family members or family-level non-segregation evidence is documented.	cspec
BP1	N/A	Not applicable: the PTEN specification marks BP1 not applicable, and this variant has no protein consequence rather than a benign missense change.	cspec
BP2	Not assessed	Not assessed: no affected-proband, phase, or cis/trans observation links NM_000314.8:c.-638C>T to another pathogenic or likely pathogenic PTEN variant.	cspec
BP3	N/A	Not applicable: the PTEN VCEP explicitly excludes BP3, and c.-638C>T is a 5′-UTR substitution rather than an in-frame deletion in a repetitive protein region.	cspec vcep_pvs1_decisiontree_pten
BP4	N/A	Not applicable: c.-638C>T is a 5' untranslated-region variant, outside the PTEN VCEP BP4 scope for missense or splice-region/intronic variants.	cspec
BP5	Not assessed	Not assessed: no two qualifying cases with a highly penetrant alternate diagnosis and non-overlapping PTEN history are documented for this variant.	cspec
BP6	N/A	Not applicable: the PTEN VCEP excludes BP6, and the exact variant has no ClinVar record or Expert Panel benign classification.	cspec clinvar
BP7	N/A	Not applicable: c.-638C>T is a 5' untranslated-region variant, not a synonymous variant within the PTEN VCEP BP7 scope.	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.