Variant classification summary

NM_000314.8:c.585_586del

PTEN · NP_000305.3:p.(Phe195LeufsTer6) · NM_000314.8

GRCh37: chr10:89711966 TTC>T · GRCh38: chr10:87952209 TTC>T

Gene: PTEN Transcript: NM_000314.8

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Phe195LeufsTer6)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic evidence: PVS1 very strong supports loss of function from a premature stop at p.200, before the VCEP p.D375 threshold.

2

Likely Pathogenic evidence: PM2 supporting is met because the variant is absent from gnomAD v2.1 and v4.1.

Final determination: Under Rule20 of the ClinGen PTEN Expert Panel Version 3.2 framework, one Pathogenic.Very Strong criterion plus one Pathogenic.Supporting criterion yields a Likely Pathogenic classification.

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	Met	Met at very strong strength: the frameshift creates a stop at p.200, well 5' of the VCEP p.D375 NMD threshold in NM_000314.8.	cspec vcep_pvs1_decisiontree_pten pvs1_variant_assessment
PS1	N/A	Not applicable: the variant is a frameshift, not a same-amino-acid missense change or a same-position pathogenic splicing variant.	cspec
PS2	Not assessed	Not assessed: no documented de novo observation with confirmed maternity and paternity, disease, and absence of family history is available.	cspec
PS3	Not assessed	Not assessed: mmc2 Table S2 contains no matching frameshift entry, and no reviewed paper provides variant-specific functional evidence meeting a PS3 threshold.	cspec vcep_mmc2 PMID:29706350 PMID:11237521 PMID:17218262
PS4	Not assessed	Not assessed: no VCEP-qualified phenotype-specific proband score or case-control odds ratio, p-value, and confidence interval is available.	cspec
PM1	Not met	Not met: residue 195 is outside the VCEP catalytic motifs 90-94, 123-130, and 166-168, and no hotspot was reported.	cspec
PM2	Met	Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, satisfying the VCEP's <0.00001 (0.001%) PM2 population-frequency requirement.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the PTEN VCEP specification explicitly designates PM3 as not applicable.	cspec
PM4	N/A	Not applicable: this frameshift causes premature termination at p.200, whereas PTEN PM4 is limited to in-frame length changes and stop-loss extensions.	cspec pvs1_variant_assessment
PM5	N/A	Not applicable: PM5 requires a missense change, whereas NM_000314.8:c.585_586del is a frameshift.	cspec
PM6	Not assessed	Not assessed: no de novo observation, disease status, family-history assessment, or parental-confirmation data are documented for the required PM6 thresholds.	cspec
PP1	Not assessed	Not assessed: no affected family members or countable segregation meioses are documented for the VCEP minimum of 3 meioses.	cspec
PP2	N/A	Not applicable: PP2 is limited by the VCEP rule to missense variants, and this variant is a frameshift.	cspec
PP3	N/A	Not applicable: the variant is a coding frameshift, whereas PTEN PP3 covers synonymous or intronic splice-impact variants and missense variants with REVEL > 0.7.	cspec
PP4	N/A	Not applicable: the PTEN VCEP marks PP4 not applicable and incorporates phenotype specificity into PS4 Use 2.	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: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the >0.00056 (0.056%) BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so its frequency is not within either VCEP BS1 interval.	cspec gnomad_v2 gnomad_v4
BS2	Not met	Not met: no homozygous observations are reported in gnomAD v2.1 or v4.1, while the VCEP requires one confirmed or two unconfirmed observations.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: mmc2 Table S2 contains no matching frameshift entry, and no reviewed paper provides variant-specific functional evidence showing preserved protein function.	cspec vcep_mmc2 PMID:29706350 PMID:11237521 PMID:17218262
BS4	Not assessed	Not assessed: no affected-family non-segregation observation is documented for either the one-family or two-family VCEP BS4 threshold.	cspec
BP1	N/A	Not applicable: the ClinGen PTEN VCEP specification marks BP1 as Not Applicable.	cspec
BP2	Not assessed	Not assessed: no phase or allelic observations establish trans with one pathogenic variant or three cis/unknown-phase observations with different PTEN variants.	cspec
BP3	N/A	Not applicable: the PTEN VCEP explicitly marks BP3 as Not Applicable for this framework.	cspec
BP4	N/A	Not applicable: the variant is a coding frameshift, whereas PTEN BP4 covers synonymous or intronic variants and missense variants with REVEL < 0.5.	cspec
BP5	Not assessed	Not assessed: no two qualifying alternate-molecular-basis cases with highly penetrant disease and non-overlapping PTEN histories are documented.	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 an exonic coding frameshift, whereas PTEN BP7 covers synonymous or intronic variants at or beyond +7/-21.	cspec

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