Variant classification summary

NM_000314.8:c.105G>T

PTEN · NP_000305.3:p.(Met35Ile) · NM_000314.8

GRCh37: chr10:89653807 G>T · GRCh38: chr10:87894050 G>T

Gene: PTEN Transcript: NM_000314.8

Final call

VUS

PM1 moderate PM2 supporting PP3 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Met35Ile)

gnomAD AF

0.0 (v4.1)

ClinVar

Likely pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM1 moderate: p.Met35Ile lies in a reported statistically significant PTEN mutational hotspot.

2

PM2 supporting: the variant is absent from gnomAD v2.1 and has allele frequency 0.0 in gnomAD v4.1.

3

PP3 supporting: the REVEL score is 0.947, exceeding the PTEN VCEP threshold of 0.7.

Final determination: Under the PTEN Expert Panel Version 3.2 framework, PM1 moderate plus PM2 and PP3 supporting does not meet any pathogenic or benign rule, so the result is 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.105G>T produces missense p.Met35Ile, whereas the PTEN PVS1 decision tree covers null, splice-site, copy-number, and initiation-codon variants.	cspec vcep_pvs1_decisiontree_pten
PS1	Not assessed	Not assessed: Met35Arg and Met35Thr are alternate changes at residue 35, but neither is the identical pathogenic Met35Ile change required by PS1.	cspec vcep_mmc2 clinvar
PS2	Not assessed	Not assessed: no proband-level de novo finding, confirmed maternity and paternity, disease status, or family-history data are available.	cspec
PS3	Not met	Not met: Table S2 reports high-confidence Cum_score -0.876619465 for M35I, above the PTEN PS3_Moderate threshold of ≤ -1.11.	vcep_mmc2 PMID:29706350
PS4	Not assessed	Not assessed: no variant-specific case-control counts, odds ratio, confidence interval, or PTEN phenotype-specificity score is available for c.105G>T.	cspec
PM1	Met	Met: PTEN M35 is reported in a statistically significant hotspot, satisfying the VCEP PM1 hotspot path despite lying outside listed catalytic motifs.	cspec
PM2	Met	Met at supporting strength: gnomAD v4.1 AF is 0.0 (0/1,612,312 alleles), below the <0.00001 PM2 threshold, and the variant is absent from gnomAD v2.1.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the PTEN VCEP explicitly designates PM3 as not applicable to PTEN.	cspec
PM4	N/A	Not applicable: p.Met35Ile is a missense substitution with no protein-length change, while PTEN PM4 is limited to in-frame indels and stop-loss variants.	cspec
PM5	Not assessed	Not assessed: Met35Arg is pathogenic at the same residue, but the required BLOSUM62 comparison for Met35Ile is unavailable.	cspec vcep_mmc2 PMID:21828076 PMID:25875300
PM6	Not assessed	Not assessed: no presumed de novo observations, proband disease status, or family-history information are available for the PM6 requirements.	cspec
PP1	Not assessed	Not assessed: no affected relatives, co-segregation observations, or meioses are documented against the PTEN VCEP thresholds of 3, 5, or 7.	cspec
PP2	Not assessed	Not assessed: the evidence does not establish both VCEP PP2 requirements—low benign missense variation and a common missense disease mechanism.	cspec
PP3	Met	Met: REVEL score 0.947 exceeds the PTEN VCEP missense PP3 threshold of >0.7.	cspec revel
PP4	N/A	Not applicable: the PTEN VCEP incorporates phenotype specificity into PS4 Use 2 instead of applying PP4.	cspec
PP5	N/A	Not applicable: the PTEN VCEP states that PP5 is not for use under the VCEP Review Committee recommendation.	cspec
BA1	Not met	Not met: gnomAD v4.1 total allele frequency is 0.0 (0/1,612,312 alleles), below the >0.00056 BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 allele frequency is 0.0, below the PTEN VCEP BS1 supporting interval beginning at 0.0000043.	cspec gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD v4.1 reports 0 homozygotes, and no qualifying healthy or PHTS-unaffected homozygous observation is available.	cspec gnomad_v4
BS3	Not met	Not met: Table S2 reports high-confidence Cum_score -0.876619465 for M35I, below the PTEN BS3_Supporting requirement of phosphatase activity >0.	vcep_mmc2 PMID:29706350
BS4	Not assessed	Not assessed: no affected family members with negative variant testing are documented in one family or across two families.	cspec
BP1	N/A	Not applicable: the PTEN VCEP explicitly marks BP1 as Not Applicable.	cspec
BP2	Not assessed	Not assessed: no documented trans observation or three qualifying cis/phase-unknown observations with different pathogenic PTEN variants are available.	cspec
BP3	N/A	Not applicable: the PTEN VCEP specification explicitly marks BP3 as Not Applicable for this framework.	cspec
BP4	Not met	Not met: REVEL score 0.947 is above, not below, the PTEN VCEP missense BP4 threshold of <0.5.	cspec revel
BP5	Not assessed	Not assessed: no two qualifying cases with a highly penetrant alternate diagnosis and non-overlapping PTEN history are documented for c.105G>T.	cspec
BP6	N/A	Not applicable: the PTEN VCEP states that BP6 is not for use under the VCEP Review Committee recommendation.	cspec
BP7	N/A	Not applicable: the variant is missense and exonic, whereas PTEN BP7 covers only synonymous or intronic variants at or beyond +7/-21.	cspec

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