NM_000314.8:c.722T>C

PTEN · NP_000305.3:p.(Phe241Ser) · NM_000314.8

GRCh37: chr10:89717697 T>C · GRCh38: chr10:87957940 T>C

Gene: PTEN Transcript: NM_000314.8

Final call

VUS

PS3_Moderate PM2_Supporting PP2 PP3

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Phe241Ser)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The PTEN c.722T>C (p.Phe241Ser) variant has been observed in somatic cancers in COSMIC (COSV64294827, 5 occurrences) and has not been reported in the current ClinVar record set.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, with an observed allele frequency of 0, which is below the PTEN Expert Panel PM2_Supporting threshold of <0.00001 (0.001%).

Functional studies support a damaging effect on PTEN, including a Mighell et al. phosphatase assay result of Cum_score -2.399 with High_conf=True, which is below the PTEN Expert Panel PS3_Moderate threshold of <= -1.11; OncoKB also describes the variant as Likely Oncogenic with a likely loss-of-function effect.

Computational evidence supports a deleterious effect for the missense change because the REVEL score is 0.858, above the PTEN Expert Panel PP3 threshold of >0.7, while SpliceAI predicts no significant splice effect with a maximum delta score of 0.01.

Final determination: PS3_Moderate with PM2_Supporting, PP2, and PP3 does not meet the PTEN final-classification threshold for likely pathogenic or pathogenic, and no benign combination rule is met; therefore this variant is classified as a variant of uncertain significance.

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	This is a missense variant, not a nonsense, frameshift, canonical +/-1,2 splice, initiation codon, or exon-level loss-of-function variant, so the PTEN-specific PVS1 decision tree does not apply.	cspec pvs1_gene_context pvs1_variant_assessment vcep_p_v_s_1___d_e_c_i_s_i_o_n_t_r_e_e___p_t_e_n
PS1	Not met	No different nucleotide change producing the same PTEN p.(Phe241Ser) amino acid substitution was identified as a previously established pathogenic variant, so PS1 is not met.	clinvar vcep_m_m_c_2
PS2	Not assessed	No proven de novo observation with confirmed maternity and paternity in an affected individual and no family history was identified, so PS2 cannot be applied from the available evidence.	vcep_m_m_c_2
PS3	Met	This missense variant showed reduced PTEN function in the Mighell et al. phosphatase assay, with Cum_score -2.399 and High_conf=True; this is below the PTEN Expert Panel PS3_Moderate threshold of <= -1.11 and supports a damaging effect on PTEN function.	vcep_m_m_c_2 oncokb PMID:21828076 PMID:25527629 PMID:32350270
PS4	Not assessed	Available evidence does not provide a PTEN phenotype specificity score, a qualifying case-control comparison, or sufficiently detailed germline proband data to apply PS4.	clinvar vcep_m_m_c_2
PM1	Not met	PTEN p.(Phe241Ser) affects residue 241, which is outside the PTEN catalytic motifs defined for PM1 (residues 90-94, 123-130, and 166-168), so PM1 is not met.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed allele frequency is 0, which is below the PTEN Expert Panel PM2_Supporting threshold of <0.00001 (0.001%).	gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable for the PTEN Expert Panel framework.	cspec
PM4	N/A	This variant is a missense substitution and does not cause an in-frame insertion, in-frame deletion, stop-loss, or protein extension, so PM4 does not apply.	cspec
PM5	Not met	No different pathogenic or likely pathogenic missense change at PTEN residue Phe241 was identified, so PM5 is not met.	clinvar vcep_m_m_c_2
PM6	Not assessed	One curated de novo observation was identified, but the available summary does not document absence of family history or enough independent de novo observations to meet the PTEN Expert Panel PM6 thresholds.	vcep_m_m_c_2
PP1	Not assessed	No segregation data with informative meioses were identified, so PP1 cannot be applied.
PP2	Met	This is a missense variant in PTEN, a gene for which missense variants are a common disease mechanism and benign missense variation is relatively constrained, so PP2 is met.	cspec
PP3	Met	Computational evidence supports a deleterious effect for this missense variant because the REVEL score is 0.858, which is above the PTEN Expert Panel PP3 threshold of >0.7.	revel
PP4	N/A	PP4 is not applicable in the PTEN Expert Panel framework because phenotype specificity is incorporated into PS4 scoring.	cspec
PP5	N/A	PP5 is not applicable in the PTEN Expert Panel framework.	cspec
BA1	Not met	This variant is absent from gnomAD, so the observed allele frequency is 0, which is below the PTEN Expert Panel BA1 threshold of >0.00056 (0.056%).	gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD, so the observed allele frequency is 0, which is below the PTEN Expert Panel BS1 thresholds of >=0.0000043 and therefore does not support a benign frequency-based interpretation.	gnomad_v2 gnomad_v4
BS2	Not assessed	No homozygous observation in a healthy or PTEN hamartoma tumor syndrome-unaffected individual was identified, so BS2 cannot be applied.
BS3	Not met	Available functional evidence does not show normal PTEN function. In the Mighell et al. assay, this variant had Cum_score -2.399, which is not above the PTEN Expert Panel BS3_Supporting threshold of >0 and therefore does not support BS3.	vcep_m_m_c_2 oncokb
BS4	Not assessed	No lack-of-segregation data in affected family members were identified, so BS4 cannot be applied.
BP1	N/A	BP1 is not applicable in the PTEN Expert Panel framework.	cspec
BP2	Not assessed	No phase data showing this variant in trans with a pathogenic PTEN variant or repeated in cis/phase-unknown observations with pathogenic PTEN variants were identified, so BP2 cannot be applied.
BP3	N/A	BP3 is not applicable for PTEN in the Expert Panel framework.	cspec
BP4	Not met	Computational evidence does not support a benign interpretation for this missense variant because the REVEL score is 0.858, which is above the PTEN Expert Panel BP4 threshold of <0.5, even though SpliceAI predicts no meaningful splice effect with a max delta score of 0.01.	revel spliceai
BP5	Not assessed	No evidence was identified that this variant was found in at least two cases with a separate highly penetrant molecular diagnosis and non-overlapping PTEN-related phenotype, so BP5 cannot be applied.
BP6	N/A	BP6 is not applicable in the PTEN Expert Panel framework.	cspec
BP7	N/A	This is not a synonymous or qualifying intronic variant, so BP7 does not apply.	cspec

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