PTEN c.743_745del, p.Pro248_Val249delinsLeu
NM_000314.8:c.743_745del
Variant of Uncertain Significance (VUS)
This in-frame deletion/insertion variant in PTEN is absent from population databases and computationally predicted to have no impact (PM2_Supporting, BP4_Supporting). No other supporting evidence for pathogenicity or benignity is available. The final classification remains Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
BP4
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.743_745del
Protein Change
P248_V249delinsL
Location
Exon 7
(Exon 7 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.743_745del
Active Tracks
ConservationRefSeqClinVargnomAD
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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
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines and the PTEN PVS1 decision tree, PVS1 requires: "Null Variant (nonsense, frameshift, start codon, splicing +1/2, startgain, single or multi-exon deletion) in a gene where loss of function is a known mechanism of disease." The evidence for this variant shows: it is an in-frame deletion/insertion (P248_V249delinsL) that does not result in a null allele. Therefore, this criterion is not applied because the variant does not meet the definition of a null variant under the PTEN PVS1 decision tree.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 requires: "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, where in silico models predict impact equal to or greater than the known pathogenic variant." The evidence for this variant shows: there is no previously established pathogenic PTEN variant at residues 248–249. Therefore, this criterion is not applied because the variant does not match any known pathogenic amino acid change at this position.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, PS2 requires: "De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history." The evidence for this variant shows: no de novo occurrence data are available. Therefore, this criterion is not applied due to lack of confirmed de novo evidence.
PS3
PS3 (Not Applied) Strength Modified
According to PTEN pre-processing, the finding for PS3 is: "The PTEN P248_V249delinsL variant has not been functionally characterized." The evidence for this variant shows: no well-established in vitro or in vivo functional studies assessing impact on PTEN function are available. Therefore, this criterion is not applied because functional data are missing.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 at Strong strength requires: "Probands with specificity score 4–15.5 OR prevalence of the variant in affected individuals significantly increased compared with controls." The evidence for this variant shows: no case‐level or cohort data documenting multiple probands or increased prevalence. Therefore, this criterion is not applied due to absence of proband data.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1 requires: "Located in a mutational hot spot and/or critical and well-established functional domain. Defined to include residues in catalytic motifs: 90–94, 123–130, 166–168." The evidence for this variant shows: P248_V249delinsL lies outside the PTEN catalytic motifs. Therefore, this criterion is not applied because the variant is not in a defined hot spot or critical domain.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Absent in population Databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population. If multiple alleles are present within any subpopulation, allele frequency in that subpopulation must be <0.00002 (0.002%)." The evidence for this variant shows: it is absent from gnomAD, ESP, 1000 Genomes, and other large population databases. Therefore, this criterion is applied at Supporting strength because the variant is essentially absent from controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 requires: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows: PTEN‐related disorders are autosomal dominant and no trans data exist. Therefore, this criterion is not applied because it is not relevant to a dominant PTEN variant.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, PM4 requires: "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Applies to in-frame insertions or deletions impacting at least one residue in a catalytic motif." The evidence for this variant shows: the in-frame deletion/insertion at residues 248–249 does not affect a catalytic motif. Therefore, this criterion is not applied because it does not meet the motif requirement.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, PM5 requires: "Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic has been seen before." The evidence for this variant shows: it is an in-frame indel, not a missense substitution, and no pathogenic missense at this site exists. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, PM6 requires: "Assumed de novo, without confirmation of paternity and maternity, in a proband with the disease and no family history." The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 requires: "Co-segregation with disease in multiple affected family members." The evidence for this variant shows: no segregation data are reported. Therefore, this criterion is not applied due to absence of family segregation information.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 requires: "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: it is an in-frame indel, not a missense change. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 requires: "Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Splicing variants: Concordance of SpliceAI and VarSeak; Missense: REVEL > 0.7." The evidence for this variant shows: SpliceAI score 0.04 (no impact) and no deleterious in silico predictions. Therefore, this criterion is not applied because computational evidence does not support deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 requires: "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 or family history data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 requires: "Reputable source reports variant as pathogenic." The evidence for this variant shows: no entries in ClinVar or other databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 requires: "gnomAD Filtering allele frequency >0.00056 (0.056%)." The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 requires: "gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%)." The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 requires: "Observed in the homozygous state in a healthy or PHTS-unaffected individual." The evidence for this variant shows: no homozygous observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 requires: "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function." The evidence for this variant shows: no functional assays demonstrating lack of damage. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 requires: "Lack of segregation in affected members of two or more families." The evidence for this variant shows: no segregation studies. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 requires: "Missense variant in a gene for which primarily truncating variants cause disease." The evidence for this variant shows: it is an in-frame indel, not a missense variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, BP2 requires: "Observed in trans with a pathogenic or likely pathogenic PTEN variant OR at least three observations in cis with different pathogenic PTEN variants." The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to VCEP guidelines, BP3 requires: "In-frame indels in a repetitive region without a known function." The evidence for this variant shows: P248_V249delinsL is outside a repetitive region. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product. Splicing variants: Concordance of SpliceAI and VarSeak; Missense variants: REVEL scores <0.5." The evidence for this variant shows: SpliceAI predicts no impact on splicing (score 0.04) and in silico data do not suggest deleterious effect. Therefore, this criterion is applied at Supporting strength because computational tools predict no impact on the gene product.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, BP5 requires: "Variant found in a case with an alternate molecular basis for disease, with no overlap in history." The evidence for this variant shows: no such case-level information. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 requires: "Reputable source reports variant as benign." The evidence for this variant shows: not reported in ClinVar or other databases. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 requires: "A synonymous or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact." The evidence for this variant shows: it is an in-frame coding indel, not synonymous or intronic. Therefore, this criterion is not applied.