NM_000314.8:c.745G>A

PTEN · NP_000305.3:p.(Val249Met) · NM_000314.8

GRCh37: chr10:89717720 G>A · GRCh38: chr10:87957963 G>A

Gene: PTEN Transcript: NM_000314.8

Final call

PM2_Supporting PP2

Variant details

Gene

PTEN

Transcript

NM_000314.8

Protein

NP_000305.3:p.(Val249Met)

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000314.8:c.745G>A (NP_000305.3:p.(Val249Met), p.(V249M)) is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PTEN Expert Panel PM2 threshold of <0.00001 (0.001%) and supports PM2_Supporting.

As a PTEN missense variant, p.(Val249Met) supports PP2 because missense variation is an established disease mechanism for this gene in the PTEN Expert Panel framework.

In the Mighell PTEN phosphatase assay, p.Val249Met has a cumulative score of -0.30689816, which is above the PS3_Moderate threshold of <= -1.11 and below the BS3 threshold of >0, so the available PTEN-specific functional data do not support either PS3 or BS3.

The REVEL score is 0.679, which is below the PTEN PP3 threshold of >0.7 and above the PTEN BP4 threshold of <0.5, so computational missense evidence does not support either criterion.

With PM2_Supporting and PP2 met, and no additional PTEN Expert Panel pathogenic or benign criteria satisfied, PTEN p.(Val249Met) is classified as a variant of uncertain significance.

Final determination:

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	PTEN-specific PVS1 applies to null variants and canonical splice-disrupting events; NM_000314.8:c.745G>A is a missense substitution, p.(Val249Met).	cspec vcep_p_v_s_1___d_e_c_i_s_i_o_n_t_r_e_e___p_t_e_n
PS1	Not assessed	No workspace evidence established a previously classified pathogenic PTEN variant producing the same amino-acid change p.Val249Met.
PS2	Not assessed	No confirmed de novo data were provided.
PS3	Not met	In PTEN supplementary Table S2 from Mighell et al., p.Val249Met (V249M) has Cum_score -0.30689816, which is above the PTEN EP PS3_Moderate threshold of <= -1.11; no splicing assay showing damaging impact was provided.	cspec vcep_m_m_c_2 PMID:29706350
PS4	Not assessed	The workspace did not provide qualifying PTEN phenotype-specific proband counts, specificity scores, or case-control enrichment data for this variant.	cspec clinvar
PM1	Not met	PTEN PM1 is restricted to catalytic motif residues 90-94, 123-130, and 166-168; Val249 lies outside these defined motifs.	cspec
PM2	Met	The variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which is below the PTEN EP PM2 threshold of <0.00001 (0.001%) for population data and supports PM2_Supporting.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in the PTEN Expert Panel specification.	cspec
PM4	N/A	PM4 applies to in-frame insertions/deletions or stop-loss variants; this variant is a missense substitution.	cspec
PM5	Not assessed	No curated evidence in the workspace established a different pathogenic or likely pathogenic missense change at PTEN codon 249 with a qualifying BLOSUM62 comparison.	cspec
PM6	Not assessed	No assumed de novo observations were provided.	cspec
PP1	Not assessed	No segregation data were provided to count informative meioses.	cspec
PP2	Met	This is a PTEN missense variant, and the PTEN Expert Panel retains PP2 for missense changes in a gene where missense variation is a recognized disease mechanism.	cspec
PP3	Not met	For PTEN missense variants, PP3 requires REVEL >0.7; the assembled REVEL score is 0.679, so this threshold is not reached.	cspec
PP4	N/A	PP4 is not applicable in the PTEN Expert Panel specification because phenotype specificity is incorporated into PS4.	cspec
PP5	N/A	PP5 is not applicable in the current ClinGen framework.	cspec
BA1	Not met	BA1 requires gnomAD filtering allele frequency >0.00056 (0.056%); this variant is absent from gnomAD v2.1 and v4.1.	cspec gnomad_v2 gnomad_v4
BS1	Not met	BS1 requires a gnomAD filtering allele frequency from 0.000043 to 0.00056 for strong strength or from 0.0000043 to 0.000043 for supporting strength; this variant is absent from gnomAD v2.1 and v4.1.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No homozygous observations in healthy or PHTS-unaffected individuals were provided.	cspec
BS3	Not met	In the PTEN Mighell assay, BS3_Supporting requires phosphatase activity >0; p.Val249Met has Cum_score -0.30689816, so it does not meet the benign functional threshold, and no splicing assay showing no effect was provided.	cspec vcep_m_m_c_2 PMID:29706350
BS4	Not assessed	No lack-of-segregation evidence was provided.	cspec
BP1	N/A	BP1 is not applicable in the PTEN Expert Panel specification.	cspec
BP2	Not assessed	No phase data with a pathogenic or likely pathogenic PTEN variant were provided.	cspec
BP3	N/A	BP3 is not applicable in the PTEN Expert Panel specification.	cspec
BP4	Not met	For PTEN missense variants, BP4 requires REVEL <0.5; the assembled REVEL score is 0.679, so the benign computational threshold is not met.	cspec
BP5	Not assessed	No evidence of an alternate highly penetrant molecular diagnosis with non-overlapping PTEN phenotype was provided.	cspec
BP6	N/A	BP6 is not applicable in the current ClinGen framework.	cspec
BP7	N/A	BP7 applies to synonymous or qualifying intronic variants; NM_000314.8:c.745G>A is a missense variant.	cspec spliceai

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.