Variant classification summary

NM_000314.8:c.388C>T

PTEN · NP_000305.3:p.(Arg130Ter) · NM_000314.8

GRCh37: chr10:89692904 C>T · GRCh38: chr10:87933147 C>T

Gene: PTEN Transcript: NM_000314.8

Final call

Pathogenic

PVS1 very strong PS3 moderate PM1 moderate PM2 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Arg130Ter)

gnomAD AF

2.4787140431544115e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PVS1 (very strong) supports loss of function from the exon 5 p.Arg130Ter nonsense variant.

2

Pathogenic: PS3 (moderate) is supported by the high-confidence phosphatase score of -3.488113982.

3

Pathogenic: PM1 (moderate) applies because Arg130 lies in the defined catalytic motif.

4

Pathogenic: PM2 (supporting) applies because gnomAD v4.1 allele frequency is 2.48e-06.

Final determination: Under the PTEN VCEP Version 3.2 criteria-combination framework, Rule2 is satisfied by one very strong pathogenic criterion (PVS1) and at least two moderate pathogenic criteria (PS3 and PM1).

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: exon 5 nonsense p.Arg130Ter occurs at codon 130, 245 residues 5' of the VCEP p.D375 NMD threshold.	pvs1_variant_assessment vcep_pvs1_decisiontree_pten vcep_mmc2
PS1	Not assessed	Not assessed: no qualifying alternate-nucleotide p.Arg130Ter or same-position pathogenic splice-site comparator is documented.
PS2	Not assessed	Not assessed: one de novo R130X observation lacked documented maternity and paternity confirmation and an explicit no-family-history statement required by the VCEP.	cspec PMID:11918710
PS3	Met	Met at moderate strength: high-confidence Mighell phosphatase assay score was -3.488113982, below the PTEN VCEP PS3 threshold of ≤ -1.11.	vcep_mmc2 PMID:29706350 cspec
PS4	Not assessed	Not assessed: Variant-specific case-control counts and VCEP phenotype-specificity scores are unavailable, so PS4 cannot be assigned from the reported patient observations.	cspec PMID:11918710 PMID:24345843 PMID:16773562 PMID:22266152
PM1	Met	Met, Moderate: residue 130 lies within the VCEP-defined P-loop/phosphatase core catalytic motif spanning residues 123-130.	cspec
PM2	Met	Met at Supporting: gnomAD v4.1 total allele frequency is 2.48e-06, below the PTEN PM2 threshold of 0.00001.	cspec gnomad_v4 gnomad_v2
PM3	N/A	Not applicable: the PTEN VCEP explicitly designates PM3 as not applicable.	cspec
PM4	N/A	Not applicable: the variant is a nonsense stop-gain, whereas PTEN PM4 covers in-frame length changes, stop-loss variants, and protein extensions.	cspec pvs1_variant_assessment
PM5	N/A	Not applicable: the variant is nonsense, p.Arg130Ter, whereas the VCEP PM5 rule requires a missense change.	cspec
PM6	Not assessed	Not assessed: one parent-negative R130X observation was reported, but no explicit no-family-history statement supports the VCEP PM6 requirement.	cspec PMID:11918710
PP1	Not assessed	Not assessed: no variant-specific segregation series with three or more meioses is documented for R130X/c.388C>T.	cspec PMID:11918710
PP2	N/A	Not applicable: p.Arg130Ter is a nonsense variant, while the VCEP PP2 rule is explicitly limited to missense variants.	cspec
PP3	N/A	Not applicable: NM_000314.8:c.388C>T is a nonsense variant, while the VCEP PP3 rule names only splicing and missense variant subpaths.	cspec
PP4	N/A	Not applicable: The PTEN VCEP incorporates phenotype specificity into PS4 Use 2 and excludes independent PP4 application.	cspec
PP5	N/A	Not applicable: The PTEN VCEP explicitly prohibits PP5 use, regardless of available pathogenic reports or ClinVar submissions.	cspec
BA1	Not met	Not met: gnomAD v4.1 filtering allele frequency is 2.8e-07, below the 0.00056 BA1 threshold.	cspec gnomad_v4 gnomad_v2
BS1	Not met	Not met: gnomAD v4.1 filtering allele frequency is 2.8e-07, below the 0.0000043 BS1-Supporting lower threshold.	cspec gnomad_v4 gnomad_v2
BS2	Not met	Not met: gnomAD v2.1 and v4.1 each report zero homozygotes for this variant.	cspec gnomad_v2 gnomad_v4
BS3	Not met	Not met: the high-confidence Mighell phosphatase score was -3.488113982, whereas the PTEN VCEP BS3 supporting threshold requires activity >0.	vcep_mmc2 PMID:29706350 cspec
BS4	Not assessed	Not assessed: no affected non-carrier is documented; unaffected non-carriers do not satisfy the VCEP's lack-of-segregation rule.	cspec PMID:11918710
BP1	N/A	Not applicable: the PTEN VCEP explicitly states that BP1 is not applicable to PTEN.	cspec
BP2	Not assessed	Not assessed: no qualifying trans observation or three cis/phase-unknown observations with different pathogenic PTEN variants are documented.	cspec PMID:11918710
BP3	N/A	Not applicable: the PTEN VCEP marks BP3 Not Applicable, and this variant is a coding nonsense stop-gain rather than a repeat-region in-frame deletion.	cspec pvs1_variant_assessment
BP4	N/A	Not applicable: NM_000314.8:c.388C>T is a nonsense variant, outside the VCEP BP4 rule's named splicing and missense subpaths.	cspec
BP5	Not assessed	Not assessed: No two cases with a highly penetrant alternate molecular basis and non-overlapping PTEN history are documented for BP5.	cspec
BP6	N/A	Not applicable: The PTEN VCEP explicitly prohibits BP6 use, regardless of any benign assertion from a reputable source.	cspec
BP7	N/A	Not applicable: NM_000314.8:c.388C>T is a coding nonsense variant, whereas BP7 is limited to synonymous or intronic variants at or beyond +7/-21.	cspec

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