PTEN c.610C>G, p.Pro204Ala
NM_000314.8:c.610C>G
COSMIC ID: COSM9211437
Likely Pathogenic
Final classification is Likely Pathogenic based on applied evidence from PS3 (Moderate), PM2 (Supporting), PM5 (Moderate), PP3 (Supporting), and PP5 (Supporting). The functional assay score along with computational and reputable source data support a deleterious effect on PTEN function.
ACMG/AMP Criteria Applied
PS3
PM2
PM5
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.610C>G
Protein Change
P204A
Location
Exon 6
(Exon 6 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 204: P204S
Alternate Identifiers
COSM9211437
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.610C>G
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 rare in the population (0.000000% MAF).
Classification
2 publications
Likely Pathogenic
Based on 3 submitter reviews in ClinVar
Submitter Breakdown
1 LP
2 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (2)
PTEN c.610C>G (p.Pro204Ala) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PM6_S: One proband with presumed de novo occurrence (maternity/paternity not confirmed) for a patient with highly specific phenotype. (internal laboratory contributor SCV000222125.7) PS3_M: Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -1.675 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350). PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor SCV000222125.7) PM2_P: Absent in large sequenced populations (PMID 27535533). PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PP3: REVEL score > 0.7 (score of this variant = 0.881)
This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 204 of the PTEN protein (p.Pro204Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autism and/or macrocephaly (PMID: 31594918, 33801456). ClinVar contains an entry for this variant (Variation ID: 189415). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PTEN protein function. Experimental studies have shown that this missense change affects PTEN function (PMID: 29706350). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratories) and as Pathogenic by Clingen PTEN Variant Curation Expert Panel, Clingen expert panel.
Expert Panel Reviews
Pathogenic
Clingen PTEN Variant Curation Expert Panel, Clingen
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
ClinVar reports other pathogenic variants at position 204: P204S
PM5 criterion applied.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.881
0.881
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:
mutationtaster: Dmetasvm: Dmetalr: Dprimateai: D
Benign:
CADD: 5.40
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the 'PVS1 decision tree' states that loss‐of‐function variants (e.g. nonsense, frameshift, canonical ±1 or 2 splice sites) are required for applying PVS1. The rule/finding for PVS1 is: 'Use PTEN PVS1 decision tree for truncating variants.' The evidence for this variant shows it is a missense change (P204A) and does not meet loss‐of‐function criteria. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS1 is applied when there is the same amino acid change as a previously established pathogenic variant regardless of nucleotide change. The rule/finding is: 'Same amino acid change as a known pathogenic variant.' The evidence for this variant shows a different nucleotide change and no identical protein change reported. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 is used for de novo variants (with confirmed maternity and paternity) in a patient with the disease. The rule/finding is: 'De novo occurrence with confirmed parentage.' The evidence for this variant does not include any de novo occurrence data. Therefore, this criterion is not applied.
PS3
PS3 (Moderate) Strength Modified
According to PTEN Pre-processing guidelines, the rule for PS3 is: 'Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product with phosphatase activity ≤ -1.11 per Mighell et al. 2018.' The evidence for this variant shows a functional score of -1.6753, which is below the -1.11 threshold. Therefore, PS3 is applied at Moderate strength.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS4 requires that the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls. The rule/finding is: 'Significant prevalence difference in affected individuals.' The evidence for this variant does not provide such epidemiological data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM1 is applied for variants located in a mutational hot spot or critical functional domain (e.g., catalytic motifs 90-94, 123-130, 166-168 as specified for PTEN by VCEP). The rule/finding is: 'Located in a mutational hot spot or critical domain.' The evidence for this variant does not indicate that it lies within such a region. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines for PM2, the rule is: 'Absent in population Databases present at <0.00001 allele frequency.' The evidence for this variant shows a MAF = 0% and the variant is not observed in gnomAD. Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 is applicable for recessive disorders where a variant is observed in trans with a pathogenic variant. The rule/finding is: 'For recessive disorders, evidence of occurrence in trans with a pathogenic variant.' Since PTEN is primarily associated with a dominant mechanism and no such evidence is provided, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 is used for protein length changes due to in-frame deletions/insertions in non-repeat regions or stop-loss variants. The rule/finding is: 'Protein length change due to in-frame events.' The evidence for this variant, being a missense change, does not involve a protein length change. Therefore, PM4 is not applied.
PM5
PM5 (Moderate)
According to VCEP guidelines for PM5, the rule is: 'Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before, with similar or lower BLOSUM62 score.' The evidence for this variant shows a novel missense change at amino acid residue P204 where a different pathogenic missense change has been reported. Therefore, PM5 is applied at Moderate strength.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 is applied for assumed de novo variants without full confirmation of parentage. The rule/finding is: 'Assumed de novo occurrence.' The evidence for this variant does not include any de novo data. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP1 is used when there is co-segregation of the variant with disease in multiple affected family members. The rule/finding is: 'Co-segregation evidence in multiple affected individuals.' The evidence for this variant does not include segregation data. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 is applied for missense variants in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. The rule/finding is: 'Missense variant in a gene with low benign variation.' While PTEN does have pathogenic missense variants, the evidence provided does not specifically invoke PP2 criteria. Therefore, PP2 is not applied.
PP3
PP3 (Supporting)
According to PTEN Pre-processing and standard ACMG guidelines, the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product; REVEL score > 0.7.' The evidence for this variant shows a REVEL score of 0.88 along with other computational tools (MutationTaster, MetaSVM, MetaLR, PrimateAI) supporting a deleterious effect. Therefore, PP3 is applied at Supporting strength.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 is applied when the patient's phenotype is highly specific for a disease with a single genetic etiology. The rule/finding is: 'Phenotype highly specific for a single genetic disorder.' The evidence for this variant does not include any such detailed clinical phenotype information. Therefore, PP4 is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, PP5 is used when a reputable source reports a variant as pathogenic without providing the underlying evidence for independent evaluation. The rule/finding is: 'Reputable source reports variant as pathogenic.' The evidence for this variant includes ClinVar submissions (with two clinical laboratories reporting uncertain significance and one reporting likely pathogenic) and a report by the ClinGen PTEN Variant Curation Expert Panel. Therefore, PP5 is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BA1 is applied when the allele frequency is above a set threshold (e.g., >0.00056 for PTEN). The rule/finding is: 'Allele frequency above 0.00056 indicates benign status.' The evidence for this variant shows a frequency of 0%. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines for BS1, the criterion is applied when the allele frequency falls within a specific range (e.g., 0.000043 to 0.00056). The rule/finding is: 'Allele frequency within benign range thresholds.' The evidence for this variant shows no such frequency and is absent from controls. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS2 is used when a variant is observed in the homozygous state in healthy individuals. The rule/finding is: 'Observation in homozygous state in unaffected individuals.' The evidence for this variant does not include any observations in healthy homozygous individuals. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to PTEN VCEP guidelines, BS3 is applied when well-established functional studies show no damaging effect on protein function. The rule/finding is: 'Functional studies showing no damaging impact.' In contrast, the evidence for this variant (as per PTEN Pre-processing) demonstrates a damaging effect with a functional score of -1.6753, supporting PS3. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS4 is applied in cases of lack of segregation in affected family members. The rule/finding is: 'Lack of segregation in affected members in two or more families.' The evidence for this variant does not include segregation data. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 is applied when a missense variant is in a gene for which truncating variants are a known mechanism of disease and missense variants are rarely pathogenic. The rule/finding is: 'Missense variant in a gene where benign missense variation is common.' However, for PTEN, missense variants are a common pathogenic mechanism. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 is applied when the variant is observed in trans with a pathogenic variant or in a context that suggests a benign role. The rule/finding is: 'Variant observed in trans with a pathogenic variant.' The evidence for this variant does not include such observations. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 is applied for in-frame insertions/deletions in a repetitive region where no functional impact is expected. The rule/finding is: 'Protein in-frame events in non-critical regions.' The evidence for this variant is a missense change and does not involve a repetitive region. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP4 is applied when multiple lines of computational evidence suggest no impact on the gene or gene product (e.g., REVEL score < 0.5). The rule/finding is: 'Computational evidence supporting benign impact.' The evidence for this variant shows a REVEL score of 0.88 and other predictors indicating deleterious impact. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 is applied when there is an alternative molecular explanation for the patient’s phenotype. The rule/finding is: 'Variant found in a case with an alternate molecular basis for the disease.' The evidence for this variant does not provide such an alternate explanation. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 is applied when a reputable source reports the variant as benign without available underlying evidence. The rule/finding is: 'Reputable benign assertion.' The evidence for this variant comes from reputable sources indicating pathogenicity. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP7 is applied exclusively to synonymous variants with no predicted impact on splicing. The rule/finding is: 'Synonymous variant with no splicing impact.' The evidence for this variant shows that it is a missense change. Therefore, BP7 is not applied.