PTEN c.740T>C, p.Leu247Ser
NM_000314.8:c.740T>C
COSMIC ID: COSM5347083
Likely Pathogenic
This variant is classified as Likely Pathogenic based on PTEN-specific functional evidence (PS3 Moderate) and multiple supporting criteria (PM2, PP2, PP3, PP5) consistent with ACMG and VCEP guidelines.
ACMG/AMP Criteria Applied
PS3
PM2
PP2
PP3
PP5
Genetic Information
Gene & Transcript Details
Gene
PTEN
Transcript
NM_000314.8
MANE Select
Total Exons
9
Strand
Forward (+)
Reference Sequence
NC_000010.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000314.7 | RefSeq Select | 9 exons | Forward |
| NM_000314.5 | Alternative | 9 exons | Forward |
| NM_000314.4 | Alternative | 9 exons | Forward |
| NM_000314.3 | Alternative | 9 exons | Forward |
| NM_000314.6 | Alternative | 9 exons | Forward |
Variant Details
HGVS Notation
NM_000314.8:c.740T>C
Protein Change
L247S
Location
Exon 7
(Exon 7 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 247 in gene PTEN
Alternate Identifiers
COSM5347083
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.740T>C
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
1 publications
Likely Pathogenic
Publications (1)
Patient, a 4 year-old girl, showed mild developmental delay, hypotonia, and dysmorphic facial features. Her last head circumference was 56.5 cm (+4.0SD). This mutation was confirmed de novo. The expression level of phosphorylated S6 ribosomal protein in her lymphoblastoid cell line was elevated.
Clinical Statement
This variant has been reported in ClinVar as Likely pathogenic by Clingen PTEN Variant Curation Expert Panel, Clingen expert panel.
Expert Panel Reviews
Likely pathogenic
Clingen PTEN Variant Curation Expert Panel, Clingen
Functional Impact
Functional Domain
Hotspot Status
Hotspot
PM1
Mutation Count
8
Reported mutations in this domain
050100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (8 mutations).
PM1 criterion applied.
Related Variants in This Domain
No evidence of other pathogenic variants at position 247 in gene PTEN
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.918
0.918
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damagingmetasvm: Dmetalr: Dprimateai: D
Benign:
CADD: 5.21
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines the rule/finding for PVS1 is: Use PTEN PVS1 decision tree for loss-of-function variants. The evidence for this variant shows: c.740T>C is a missense variant and does not introduce a premature stop or alter a canonical splice site. Therefore, this criterion is not applied because the variant is not expected to result in loss of function.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines the rule/finding for PS1 is: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change or different variant at same nucleotide position as a pathogenic splicing variant. The evidence for this variant shows: no previously established pathogenic variant resulting in Leu247Ser. Therefore, this criterion is not applied because there is no matching amino acid change reported as pathogenic.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines the rule/finding for PS2 is: Very Strong de novo or Strong de novo with confirmation of maternity and paternity. The evidence for this variant shows: no de novo occurrence data available. Therefore, this criterion is not applied because de novo status has not been established.
PS3
PS3 (Moderate) Strength Modified
According to PTEN Pre-processing guidelines the finding for PS3 is: Phosphatase activity ≤ -1.11 per Mighell et al. 2018, PMID: 29706350. The evidence for this variant shows: functional score of -1.6698 which is below the threshold of -1.11. Therefore, this criterion is applied at Moderate strength because the variant meets the PTEN-specific functional assay threshold.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines the rule/finding for PS4 is: Probands with specificity score ≥16 for Very Strong or 4–15.5 for Strong. The evidence for this variant shows: no proband specificity score data available. Therefore, this criterion is not applied because case prevalence data are lacking.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines the rule/finding for PM1 is: Located in a mutational hotspot and/or critical functional domain defined to include residues in catalytic motifs: 90-94, 123-130, 166-168. The evidence for this variant shows: Leu247 is outside of these PTEN catalytic motifs. Therefore, this criterion is not applied because the residue is not in a defined hotspot or critical domain.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines the rule/finding for PM2 is: Absent in population databases present at <0.00001 allele frequency in gnomAD. The evidence for this variant shows: variant is not found in gnomAD or other population databases. Therefore, this criterion is applied at Supporting strength because of absence from controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule/finding for PM3 is: For recessive disorders, detected in trans with a pathogenic variant supports moderate evidence. The evidence for this variant shows: PTEN-related disease is autosomal dominant and no trans observation with a pathogenic PTEN variant. Therefore, this criterion is not applied because PM3 is not relevant for dominant inheritance.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines the rule/finding for PM4 is: Protein length changes due to in-frame insertions/deletions in non-repeat regions. The evidence for this variant shows: this is a missense substitution with no change in protein length. Therefore, this criterion is not applied because there is no protein length alteration.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines the rule/finding for PM5 is: Missense change at a residue where a different missense change determined to be pathogenic has been seen before. The evidence for this variant shows: no other missense variants at Leu247 have been reported as pathogenic. Therefore, this criterion is not applied because no prior pathogenic missense at this residue is known.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines the rule/finding for PM6 is: Assumed de novo without parental confirmation. The evidence for this variant shows: no de novo or parental data. Therefore, this criterion is not applied because there is no assumed de novo evidence.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines the rule/finding for PP1 is: Co-segregation with disease in multiple affected family members. The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied because familial segregation has not been assessed.
PP2
PP2 (Supporting)
According to standard ACMG guidelines the rule/finding for PP2 is: Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. The evidence for this variant shows: PTEN is intolerant of benign missense and missense variants are known to cause PTEN-related disorders. Therefore, this criterion is applied at Supporting strength because of the gene's intolerance and disease mechanism.
PP3
PP3 (Supporting)
According to VCEP guidelines the rule/finding for PP3 is: Multiple lines of computational evidence support a deleterious effect, with REVEL score > 0.7. The evidence for this variant shows: REVEL score of 0.92, PolyPhen, MetaSVM, MetaLR, PrimateAI and Deogen2 predict damaging. Therefore, this criterion is applied at Supporting strength because of consistent damaging in silico predictions.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule/finding for PP4 is: Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology. The evidence for this variant shows: no phenotype data provided. Therefore, this criterion is not applied because phenotype specificity cannot be evaluated.
PP5
PP5 (Supporting)
According to standard ACMG guidelines the rule/finding for PP5 is: Reputable source reports variant as pathogenic but the evidence is unavailable for independent evaluation. The evidence for this variant shows: ClinVar entry by ClinGen PTEN VCEP lists Likely Pathogenic. Therefore, this criterion is applied at Supporting strength because of the reputable external assertion.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines the rule/finding for BA1 is: gnomAD filtering allele frequency > 0.00056. The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied because allele frequency is not above the threshold.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines the rule/finding for BS1 is: gnomAD allele frequency from 0.000043 up to 0.00056. The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied because the frequency is below the benign range.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines the rule/finding for BS2 is: Observed homozygous in a healthy individual. The evidence for this variant shows: no homozygous observations reported. Therefore, this criterion is not applied because no unaffected homozygotes are documented.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines the rule/finding for BS3 is: Well-established functional studies show no damaging effect, with phosphatase activity > 0. The evidence for this variant shows: measured activity is below threshold indicating damaging effect. Therefore, this criterion is not applied because functional data support damage.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines the rule/finding for BS4 is: Lack of segregation in affected members of families. The evidence for this variant shows: no segregation studies. Therefore, this criterion is not applied because segregation data are absent.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule/finding for BP1 is: Missense variant in a gene where truncating variants are the only known mechanism of disease. The evidence for this variant shows: missense is a known mechanism for PTEN-related disorders. Therefore, this criterion is not applied because missense variants are established pathogenic mechanisms.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines the rule/finding for BP2 is: Observed in trans with a pathogenic PTEN variant or multiple cis observations. The evidence for this variant shows: no trans or cis observations. Therefore, this criterion is not applied because no such observations exist.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule/finding for BP3 is: In-frame deletions/insertions in repetitive regions without known function. The evidence for this variant shows: this is a missense substitution. Therefore, this criterion is not applied because it is not an in-frame indel.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines the rule/finding for BP4 is: Multiple lines of computational evidence suggest no impact, with REVEL < 0.5. The evidence for this variant shows: REVEL is 0.92 indicating damaging effect. Therefore, this criterion is not applied because computational predictions support deleterious effect.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines the rule/finding for BP5 is: Variant found in a case with an alternate molecular basis for disease. The evidence for this variant shows: no alternate molecular basis reported. Therefore, this criterion is not applied because no such case is documented.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule/finding for BP6 is: Reputable source reports variant as benign but evidence is unavailable. The evidence for this variant shows: no reputable source reports benign. Therefore, this criterion is not applied because there is no benign assertion.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines the rule/finding for BP7 is: Synonymous variant predicted to have no splicing impact. The evidence for this variant shows: this is a missense variant. Therefore, this criterion is not applied because BP7 applies only to silent or intronic variants.