NM_000314.8:c.431A>C

PTEN · NP_000305.3:p.(Lys144Thr) · NM_000314.8

GRCh37: chr10:89692947 A>C · GRCh38: chr10:87933190 A>C

Gene: PTEN Transcript: NM_000314.8

Final call

VUS

PM2 supporting PP2 supporting

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Lys144Thr)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000314.8:c.431A>C (NP_000305.3:p.Lys144Thr) is a missense variant in exon 5 of PTEN.

This variant is absent from gnomAD v2.1 and v4.1 (PM2_Supporting per VCEP).

PTEN has a low rate of benign missense variation and missense variants are a common disease mechanism (PP2_Supporting per VCEP).

Functional data from Mighell et al. 2018 saturation mutagenesis assay shows a cumulative fitness score of -0.15 for K144T, indicating mild functional impairment that does not meet PS3 or BS3 thresholds.

REVEL score of 0.691 does not exceed the VCEP PP3 threshold of >0.7; SpliceAI predicts no splice impact.

The variant lies outside the PTEN catalytic motifs (residues 90-94, 123-130, 166-168); PM1 is not met.

This variant has been reported in ClinVar as Uncertain Significance (1 submitter, VCV2687516). It has been observed somatically in 3 cancer samples (COSMIC COSV64295211).

No case-level proband data, de novo observations, co-segregation data, or same-residue pathogenic comparator variants were identified.

With 2 supporting-level pathogenic criteria (PM2_Supporting, PP2_Supporting) and no benign criteria met, the variant does not reach the combination threshold for Likely Pathogenic or Pathogenic under the PTEN VCEP v3.2.0 rules. The variant remains a Variant of Uncertain Significance.

Final determination: No criteria-combination rule matched the adjudicated criteria in the Richards et.al., 2015 - Combining rules v3.2.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

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	NM_000314.8:c.431A>C is a missense variant (p.Lys144Thr). The PTEN VCEP PVS1 decision tree applies exclusively to null variants (nonsense, frameshift, and canonical GT-AG splice site disruptions).	vcep_pvs1_decisiontree_pten
PS1	Not met	No prior established pathogenic or likely pathogenic variant at amino acid residue Lys144 was identified. The only ClinVar entry at this position is VCV2687516, classified as Uncertain Significance.	clinvar pm5_candidates
PS2	Not assessed	No de novo observation data were identified for NM_000314.8:c.431A>C in the available evidence.
PS3	Not met	Functional data from Mighell et al. 2018 (PMID: 29706350) PTEN saturation mutagenesis assay yields a cumulative fitness score (Cum_score) of -0.15 for K144T (High_conf=True). This does not meet the VCEP PS3_Moderate threshold of <= -1.11, and the mild fitness reduction does not clearly satisfy PS3_Supporting criteria for a damaging effect.	vcep_mmc2
PS4	Not assessed	No proband counts or phenotype specificity scores were available for this variant to calculate the VCEP PS4 specificity score.
PS5	N/A	PP5 is marked Not Applicable by the ClinGen PTEN VCEP v3.2.0. The closely related PS5 criterion is not separately defined in the VCEP specification.	cspec
PM1	Not met	p.Lys144 is outside the PTEN catalytic motif residues defined by the VCEP (positions 90-94, 123-130, and 166-168 in NP_000305.3).	cspec
PM2	Met	NM_000314.8:c.431A>C is absent from gnomAD v2.1 and v4.1. Per PTEN VCEP specification, PM2 is applied at Supporting strength when allele frequency is below 0.001%.	gnomad_v2 gnomad_v4
PM5	Not met	No pathogenic or likely pathogenic missense variant at residue Lys144 was identified in ClinVar or the VCEP evidence base. The PM5 candidate search returned zero comparator variants at this residue.	pm5_candidates clinvar
PM6	Not assessed	No de novo observation data were identified for NM_000314.8:c.431A>C in the available evidence.
PP1	Not assessed	No co-segregation data were available for this variant.
PP2	Met	NM_000314.8:c.431A>C is a missense variant in PTEN, a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease, per VCEP PP2 specification.	cspec
PP3	Not met	REVEL score of 0.691 does not exceed the VCEP PP3 threshold of >0.7 for missense variants. SpliceAI predicts no splice impact (max delta 0.00). BayesDel score of 0.059 is near neutral and does not independently support a deleterious effect.	revel bayesdel spliceai
PP4	N/A	Marked Not Applicable by the ClinGen PTEN VCEP v3.2.0; phenotype specificity is incorporated into the PS4 rule specifications.	cspec
PP5	N/A	Marked Not Applicable by the ClinGen PTEN VCEP v3.2.0.	cspec
BA1	Not met	NM_000314.8:c.431A>C is absent from gnomAD. The VCEP BA1 threshold of >0.056% filtering allele frequency is not met.	gnomad_v2 gnomad_v4
BS1	Not met	NM_000314.8:c.431A>C is absent from gnomAD. The VCEP BS1_Strong threshold of >0.0043% and BS1_Supporting threshold of >0.00043% are not met.	gnomad_v2 gnomad_v4
BS2	Not assessed	No homozygous observations in healthy or PHTS-unaffected individuals were identified for this variant.
BS3	Not met	Functional data from Mighell et al. 2018 (PMID: 29706350) shows a cumulative fitness score of -0.15 for K144T, which does not satisfy the VCEP BS3_Supporting threshold of a Cum_score >0. The negative score indicates mild functional impairment rather than absence of a damaging effect.	vcep_mmc2
BS4	Not assessed	No segregation data were available to assess lack of segregation in affected family members.
BP1	N/A	Marked Not Applicable by the ClinGen PTEN VCEP v3.2.0.	cspec
BP2	Not assessed	No observations of this variant in trans or cis with other PTEN pathogenic or likely pathogenic variants were available.
BP3	N/A	Skipped per instructions — in-frame indel criterion not applicable to a substitution variant.
BP4	Not met	REVEL score of 0.691 does not meet the VCEP BP4 threshold of <0.5 for missense variants. SpliceAI predicts no splicing impact (max delta 0.00) but VCEP BP4 for splicing applies to synonymous/intronic variants, not this missense variant.	revel spliceai cspec
BP5	Not assessed	No evidence was identified of this variant occurring in a case with an alternate molecular basis for disease.
BP6	N/A	Marked Not Applicable by the ClinGen PTEN VCEP v3.2.0.	cspec
BP7	N/A	NM_000314.8:c.431A>C is a missense variant. Per VCEP specification, BP7 applies only to synonymous or intronic variants at or beyond +7/-21 positions with no predicted splice impact.	cspec

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