LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
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
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
PM2 Supporting: the variant is absent from gnomAD v4.1 (0/1,612,312 alleles).
2
PP3 Supporting: REVEL score 0.947 exceeds the PTEN VCEP threshold of >0.7.
Final determination:
The PTEN VCEP Version 3.2 framework requires one Very Strong criterion plus qualifying stronger evidence or multiple specified supporting criteria for a pathogenic call, and at least two supporting benign criteria for a likely benign call; neither requirement is met.
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: NM_000314.8:c.105G>T is missense p.(Met35Ile), whereas the PTEN tree names null, splice-site, deletion, duplication, and initiation-codon variants. |
cspec
|
| PS1 | Not met | Not met: no previously established pathogenic variant with the same amino-acid change, p.Met35Ile, was identified. |
PMID:21828076
PMID:25875300
|
| PS2 | Not assessed | Not assessed: no documented de novo observation with confirmed maternity and paternity and no family history is available. |
|
| PS3 | Not met | Not met: high-confidence M35I phosphatase Cum_score was -0.876619465, above the PTEN VCEP PS3_Moderate threshold of <= -1.11. |
cspec
vcep_mmc2
PMID:29706350
|
| PS4 | Not assessed | Not assessed: no affected-case frequency, control comparison with OR/95% CI, or PTEN phenotype-specificity score is available for p.Met35Ile. |
cspec
gnomad_v4
PMID:21828076
PMID:23788249
PMID:25356965
PMID:25645574
PMID:25875300
PMID:27854360
|
| PM1 | Not met | Not met: residue 35 is outside all VCEP-approved catalytic motifs, which are 90-94, 123-130, and 166-168. |
cspec
|
| PM2 | Met | Met at Supporting: gnomAD v4.1 total allele frequency is 0.0 (0/1,612,312), below the <0.00001 (0.001%) PM2 threshold. |
cspec
gnomad_v2
gnomad_v4
|
| PM3 | N/A | Not applicable: the PTEN VCEP explicitly marks PM3 as "Not Applicable" in Version 3.2. |
cspec
|
| PM4 | N/A | Not applicable: p.(Met35Ile) is a length-preserving missense change, while PTEN PM4 requires an in-frame indel or stop-loss variant. |
cspec
|
| PM5 | Not assessed | Not assessed: M35R is reported pathogenic, but the required BLOSUM62 comparison for p.Met35Ile is unavailable. |
vcep_mmc2
PMID:29706350
PMID:25875300
|
| PM6 | Not assessed | Not assessed: no assumed de novo observation, disease phenotype, or de novo-observation count is documented. |
|
| PP1 | Not assessed | Not assessed: no affected relatives with matching genotypes or countable meioses are documented. |
|
| PP2 | Not assessed | Not assessed: the available evidence does not establish both a low benign-missense rate and a common PTEN missense disease mechanism. |
cspec
|
| PP3 | Met | Met: REVEL score 0.947 exceeds the PTEN VCEP PP3 missense threshold of >0.7. |
cspec
revel
|
| PP4 | N/A | Not applicable: the PTEN VCEP incorporates phenotype specificity into PS4 Use 2 rather than allowing PP4. |
cspec
|
| PP5 | N/A | Not applicable: the PTEN VCEP prohibits PP5, regardless of the available single-submitter likely-pathogenic classification. |
cspec
clinvar
|
| BA1 | Not met | Not met: gnomAD v4.1 total allele frequency is 0.00000 (0/1,612,312), below the >0.00056 BA1 threshold. |
cspec
gnomad_v2
gnomad_v4
|
| BS1 | Not met | Not met: gnomAD v4.1 total allele frequency is 0.00000, below the VCEP BS1 lower bound of 0.0000043 (0.00043%). |
cspec
gnomad_v2
gnomad_v4
|
| BS2 | Not met | Not met: gnomAD v4.1 reports 0 homozygotes, and the variant is absent from gnomAD v2.1, providing no BS2 observation. |
cspec
gnomad_v2
gnomad_v4
|
| BS3 | Not met | Not met: high-confidence M35I had a negative phosphatase Cum_score of -0.876619465, not the >0 value required for BS3_Supporting. |
cspec
vcep_mmc2
PMID:29706350
|
| BS4 | Not assessed | Not assessed: no affected family members carrying the variant without the expected disease phenotype are documented. |
|
| BP1 | N/A | Not applicable: the PTEN VCEP explicitly excludes BP1 for this gene. |
cspec
|
| BP2 | Not assessed | Not assessed: no documented trans observation or three cis/phase-unknown observations with different pathogenic PTEN variants are available. |
|
| BP3 | N/A | Not applicable: the PTEN VCEP explicitly marks BP3 Not Applicable, and p.(Met35Ile) is not an in-frame indel in a repetitive region. |
cspec
|
| BP4 | Not met | Not met: REVEL score 0.947 is above, not below, the PTEN VCEP BP4 missense threshold of <0.5. |
cspec
revel
|
| BP5 | Not assessed | Not assessed: no two cases with a highly penetrant alternate diagnosis and non-overlapping PTEN personal or family histories are documented. |
cspec
|
| BP6 | N/A | Not applicable: the PTEN VCEP prohibits BP6 for this variant-interpretation framework. |
cspec
|
| BP7 | N/A | Not applicable: the variant is exonic missense, whereas PTEN VCEP BP7 covers only synonymous or intronic variants at or beyond +7/-21. |
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.