Variant classification summary

NM_000314.8:c.964A>G

PTEN · NP_000305.3:p.(Lys322Glu) · NM_000314.8

GRCh37: chr10:89720813 A>G · GRCh38: chr10:87961056 A>G

Gene: PTEN Transcript: NM_000314.8

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Lys322Glu)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1, meeting the PTEN VCEP frequency threshold.

2

PP3 supporting: REVEL 0.877 exceeds the PTEN VCEP missense threshold of >0.7.

Final determination: Under the ClinGen PTEN Expert Panel Version 3.2 framework, PM2 supporting plus PP3 supporting does not satisfy a pathogenic or benign combination 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.964A>G produces missense p.Lys322Glu, whereas the PTEN PVS1 tree covers null, splice-site, copy-number, and initiation-codon variants.	cspec vcep_pvs1_decisiontree_pten vcep_mmc2
PS1	Not assessed	Not assessed: no previously established pathogenic p.Lys322Glu or qualifying splice-site comparator is documented in the available evidence.	cspec clinvar PMID:26467025 PMID:32350270
PS2	Not assessed	Not assessed: no documented proband, disease phenotype, family history, parental testing, or maternity/paternity confirmation is available for this variant.	cspec
PS3	Not met	Not met: high-confidence Mighell phosphatase Cum_score -0.166801504 does not reach the VCEP PS3_Moderate threshold of <= -1.11.	cspec vcep_mmc2 PMID:29706350
PS4	Not assessed	Not assessed: no case-control statistics, phenotype-specific proband score, or documented clinical phenotype is available for PTEN c.964A>G.	cspec clinvar PMID:26467025 PMID:32350270
PM1	Not met	Not met: Lys322 lies outside the VCEP motifs 90-94, 123-130, and 166-168, and no statistically significant hotspot was found.	cspec
PM2	Met	Met at Supporting: the variant is absent in gnomAD v2.1 and v4.1, giving allele frequency 0 versus the VCEP PM2 threshold of <0.00001.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the PTEN Expert Panel explicitly excludes PM3 from use for PTEN.	cspec
PM4	N/A	Not applicable: p.Lys322Glu is a missense substitution with no protein-length change, not an in-frame indel or stop-loss variant.	cspec vcep_mmc2
PM5	Not assessed	Not assessed: no pathogenic or likely pathogenic alternate missense comparator at PTEN residue Lys322 is documented for the required BLOSUM62 comparison.	cspec pm5_candidates
PM6	Not assessed	Not assessed: no assumed or proven de novo observation, disease status, family history, or parental testing is documented for this variant.	cspec
PP1	Not assessed	Not assessed: no affected relatives, co-segregation observations, or meiosis count is documented for this variant.	cspec
PP2	Not assessed	Not assessed: PTEN missense status is established, but VCEP-supported evidence for both low benign-missense variation and a common missense mechanism is missing.	cspec
PP3	Met	Met: REVEL score 0.877 exceeds the PTEN VCEP PP3 missense threshold of >0.7.	cspec revel
PP4	N/A	Not applicable: the PTEN VCEP explicitly incorporates phenotype specificity into PS4 Use 2 rather than allowing PP4.	cspec
PP5	N/A	Not applicable: the PTEN VCEP prohibits PP5 use under its explicit criterion-specific instruction.	cspec
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the VCEP BA1 threshold of 0.00056.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so no allele frequency falls within either VCEP BS1 interval.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports no variant observations and provides no homozygous healthy-individual evidence required by the VCEP BS2 rule.	cspec gnomad_v2 gnomad_v4
BS3	Not met	Not met: high-confidence Mighell phosphatase Cum_score -0.166801504 is not greater than the VCEP BS3_Supporting threshold of >0.	cspec vcep_mmc2 PMID:29706350
BS4	Not assessed	Not assessed: no affected relatives, family testing, or variant-specific non-segregation result is documented.	cspec
BP1	N/A	Not applicable: the PTEN VCEP explicitly excludes BP1 for PTEN.	cspec
BP2	Not assessed	Not assessed: no documented trans phase or three cis/unknown-phase observations with different pathogenic PTEN variants are available.	cspec clinvar PMID:26467025 PMID:32350270
BP3	N/A	Not applicable: the PTEN VCEP explicitly marks BP3 not applicable, and this variant is missense rather than a repetitive-region in-frame deletion.	cspec vcep_mmc2
BP4	Not met	Not met: REVEL score 0.877 is above, rather than below, the PTEN VCEP BP4 missense cutoff of <0.5.	cspec revel
BP5	Not assessed	Not assessed: no two qualifying alternate-molecular-basis cases or non-overlapping clinical histories are documented for this variant.	cspec
BP6	N/A	Not applicable: the PTEN VCEP prohibits BP6 use under its explicit criterion-specific instruction.	cspec
BP7	N/A	Not applicable: this is an exonic missense variant, whereas PTEN VCEP BP7 covers only synonymous or sufficiently distant intronic variants.	cspec

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