Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000314.7 | RefSeq Select | 8514 nt | 845–2056 |
| NM_000314.5 | Alternative | 8719 nt | 1032–2243 |
| NM_000314.4 | Alternative | 5572 nt | 1032–2243 |
| NM_000314.3 | Alternative | 3416 nt | 1032–2243 |
| NM_000314.6 | Alternative | 8718 nt | 1032–2243 |
| NM_000314.8 | MANE Select | 8515 nt | 846–2057 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenThe p.V249M variant (also known as c.745G>A), located in coding exon 7 of the PTEN gene, results from a G to A substitution at nucleotide position 745. The valine at codon 249 is replaced by methionine, an amino acid with highly similar properties. This variant demonstrated low intracellular protein abundance on one multiplex functional assay (Matreyek KA et al. Nat Genet, 2018 06;50:874-882) but had wildtype-like phosphatase activity in a massively parallel functional assay using a humanized yeast model (Mighell TL et al. Am J Hum Genet, 2018 05;102:943-955). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
"This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.04 | -56 bp |
| Donor Loss (DL) | 0.0 | -208 bp |
| Acceptor Gain (AG) | 0.0 | -254 bp |
| Donor Gain (DG) | 0.0 | -29 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the PVS1 rule is: "Very Strong Strength: Very Strong Use PTEN PVS1 decision tree. Modification Type: Disease-specific". The variant is a missense change (c.745G>A; p.V249M) and not a null variant as defined by the PVS1 decision tree. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines, the PS1 rule is: "Strong Strength: Strong 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." There is no known pathogenic variant at codon V249 producing the same amino acid change. Therefore, PS1 is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the PS2 rule is: "Strong Strength: Strong De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history." No de novo or parental testing data are available for this variant. Therefore, PS2 is not applied.
PS3 (Not Applied)
According to PTEN Pre-processing findings, the PS3_Moderate threshold is -1.11, and the variant's phosphatase activity score is -0.3069, which did not meet the threshold. Therefore, PS3 is not applied.
PS4 (Not Applied)
According to VCEP guidelines, the PS4 rule is: "Strong Strength: Strong Probands with specificity score 4-15.5 (see text) OR The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls." No case or cohort data are available to calculate specificity scores or prevalence. Therefore, PS4 is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the PM1 rule is: "Moderate Strength: Moderate 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 (NP_000305.3)." The V249 residue is outside these defined catalytic motifs. Therefore, PM1 is not applied.
PM2 (Supporting)
According to VCEP guidelines, the PM2 rule is: "Supporting Strength: Supporting 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%)." This variant is absent from gnomAD and other population databases. Therefore, PM2 is applied at Supporting strength.
PM3 (Not Applied)
According to standard ACMG guidelines, the PM3 rule is: "For recessive disorders, detected in trans with a pathogenic variant." PTEN-related disorders are autosomal dominant and there is no evidence of trans configuration. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to VCEP guidelines, the PM4 rule is: "Moderate Strength: Moderate 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, and variants causing protein extension." This variant is a single amino acid substitution, not an in-frame indel or protein-length change. Therefore, PM4 is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the PM5 rule is: "Moderate Strength: Moderate Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic has been seen before, with BLOSUM62 score equal to or less than the known variant." No other pathogenic missense variants at residue V249 have been reported. Therefore, PM5 is not applied.
PM6 (Not Applied)
According to VCEP guidelines, the PM6 rule is: "Strong/Very Strong Strength: Assumed de novo observations without confirmation of paternity/maternity in a patient with the disease and no family history." No presumed de novo data exist. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the PP1 rule is: "Supporting/Moderate/Strong Strength: Co-segregation with disease in multiple affected family members with varying numbers of meioses observed." No family segregation data are available. Therefore, PP1 is not applied.
PP2 (Supporting)
According to standard ACMG guidelines, the PP2 rule is: "Supporting Strength: Supporting Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease." PTEN is intolerant to benign missense variation and missense changes are a well-established mechanism in PTEN-related disease. Therefore, PP2 is applied at Supporting strength.
PP3 (Not Applied)
According to VCEP guidelines, the PP3 rule is: "Supporting Strength: Supporting Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Missense variants: REVEL score > 0.7." Computational predictions for this variant are mixed and no consensus REVEL score > 0.7 is available. Therefore, PP3 is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the PP4 rule is: "Supporting Strength: Supporting Patient's phenotype or family history is highly specific for a disease with a single genetic etiology." No clinical phenotype or family history data are provided. Therefore, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the PP5 rule is: "Supporting Strength: Supporting A reputable source reports the variant as pathogenic." ClinVar reports this variant as Uncertain Significance. Therefore, PP5 is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the BA1 rule is: "Stand Alone Strength: Stand Alone gnomAD Filtering allele frequency >0.00056 (0.056%)." The variant is absent from population databases. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the BS1 rule is: "Strong Strength: Strong gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%)." The variant is absent from population databases. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the BS2 rule is: "Strong Strength: Strong Observed in the homozygous state in a healthy or PHTS-unaffected individual." No homozygous observations in healthy individuals are reported. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the BS3 rule is: "Strong Strength: Strong Well-established in vitro or in vivo functional studies shows no damaging effect on protein function." Functional assay data do not demonstrate normal function (phosphatase activity score is -0.3069, not >0). Therefore, BS3 is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the BS4 rule is: "Strong Strength: Strong Lack of segregation in affected members of two or more families." No segregation data are available. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the BP1 rule is: "Supporting Strength: Supporting Missense variant in a gene for which primarily truncating variants cause disease." Missense variants in PTEN are a known mechanism of disease. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the BP2 rule is: "Supporting Strength: Supporting Observed in trans with a pathogenic or likely pathogenic PTEN variant OR at least three observations in cis with different pathogenic/likely pathogenic PTEN variants." No cis/trans data with other PTEN variants are available. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the BP3 rule is: "Supporting Strength: Supporting In-frame deletions/insertions in a repetitive region without a known function." This is a missense substitution, not an indel. Therefore, BP3 is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the BP4 rule is: "Supporting Strength: Supporting Multiple lines of computational evidence suggest no impact on gene or gene product. Missense variants: REVEL scores < 0.5." Computational evidence is mixed and no consensus REVEL < 0.5 is available. Therefore, BP4 is not applied.
BP5 (Not Applied)
According to VCEP guidelines, the BP5 rule is: "Supporting Strength: Supporting Variant found in a case with an alternate molecular basis for disease." No such alternate molecular basis data are provided. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the BP6 rule is: "Supporting Strength: Supporting A reputable source reports the variant as benign." No reputable source lists this variant as benign. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the BP7 rule is: "Supporting Strength: Supporting A synonymous or intronic variant at or beyond +7/-21 with no splicing impact." This is a missense variant, not synonymous or intronic. Therefore, BP7 is not applied.