PTEN c.634+17C>T, p.?
NM_000314.8:c.634+17C>T
Likely Benign
This intronic +17 PTEN variant is absent from population databases, shows no computational or splicing impact, and is reported as likely benign in ClinVar. With four supporting benign criteria (PM2, BP4, BP6, BP7) and no evidence for pathogenicity, the variant is classified as Likely Benign.
ACMG/AMP Criteria Applied
PM2
BP4
BP6
BP7
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.634+17C>T
Protein Change
?
Location
Exon 6
(Exon 6 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.634+17C>T
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
Likely Benign
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (1 clinical laboratories).
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
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 1.89
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PVS1 is: 'Very Strong Use PTEN PVS1 decision tree.' The evidence for this variant shows: it is an intronic variant at +17, outside of the canonical ±1,2 splice sites. Therefore, this criterion is not applied because PVS1 applies only to null variants or canonical splice site variants per PTEN PVS1 decision tree.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: '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.' The evidence for this variant shows: it is an intronic change, not altering an amino acid nor at a nucleotide with a prior pathogenic splicing variant. Therefore, this criterion is not applied because PS1 requires an amino acid change or splicing variant at the same nucleotide.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: 'Strong 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 occurrences have been reported. Therefore, this criterion is not applied because there is no confirmed de novo evidence.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: 'Strong Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. RNA, mini-gene, or other assay shows impact on splicing.' The evidence for this variant shows: no functional studies have been performed or reported. Therefore, this criterion is not applied because required functional data are missing.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: 'Strong Probands with specificity score 4-15.5 OR prevalence significantly increased in affected individuals compared with controls.' The evidence for this variant shows: no case-level data or cohort enrichment. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: '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 evidence for this variant shows: it is intronic and not located within any defined functional domain. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: '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%).' The evidence for this variant shows: it is absent from gnomAD. Therefore, this criterion is applied at Supporting strength because it is absent from large population databases per VCEP PM2.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'For recessive disorders, detected in trans with a pathogenic variant.' The evidence for this variant shows: PTEN-related conditions are autosomal dominant and no trans observations are reported. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: 'Moderate Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.' The evidence for this variant shows: it is intronic and does not alter protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: 'Moderate Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic has been seen before. In addition, variant being interrogated must have BLOSUM62 score equal to or less than the known variant.' The evidence for this variant shows: it is intronic and not a missense change. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: 'Strong Two probands with presumed de novo occurrences (maternity/paternity not confirmed) with the disease and no family history OR one proven + two assumed de novo.' The evidence for this variant shows: no presumed de novo data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: 'Supporting Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed.' The evidence for this variant shows: no family segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP2 is: '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.' The evidence for this variant shows: it is not a missense variant. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: 'Supporting Multiple lines of computational evidence support a deleterious effect on the gene or gene product.' The evidence for this variant shows: computational predictors (SpliceAI, CADD, others) do not predict a deleterious effect. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Patient's phenotype or family history is highly specific for a disease with 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, the rule for PP5 is: 'Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.' The evidence for this variant shows: reputable sources (ClinVar) report this variant as benign. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: 'Stand Alone 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, the rule for BS1 is: 'Strong gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%).' The evidence for this variant shows: allele frequency is absent. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: 'Strong Observed in the homozygous state in a healthy or PHTS-unaffected individual. One observation if homozygous status confirmed, two if not confirmed.' The evidence for this variant shows: no homozygous observations are reported. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: 'Strong Well-established in vitro or in vivo functional studies shows no damaging effect on protein function. To be applied to intronic or synonymous variants, RNA, mini-gene or other splicing assay demonstrating no splicing impact.' The evidence for this variant shows: no such functional or splicing assays have been performed. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: 'Strong Lack of segregation in affected members of two or more families.' The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Supporting Missense variant in a gene for which primarily truncating variants are known to cause disease.' The evidence for this variant shows: it is intronic and not a missense variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: 'Supporting Observed in trans with a pathogenic or likely pathogenic PTEN variant OR at least three observations in cis and/or phase unknown with different pathogenic/likely pathogenic PTEN variants.' The evidence for this variant shows: no such observations are reported. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'Supporting In-frame deletions/insertions in a repetitive region without a known function.' The evidence for this variant shows: it is intronic and not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: 'Supporting Multiple lines of computational evidence suggest no impact on gene or gene product. Splicing variants: Concordance of SpliceAl and VarSeak Missense variants: REVEL scores < 0.5.' The evidence for this variant shows: SpliceAI predicts no splicing impact and other in silico tools (CADD 1.89, conservation) indicate benign. Therefore, this criterion is applied at Supporting strength because computational evidence supports no impact per VCEP BP4.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: 'Supporting Variant found in a case with an alternate molecular basis for disease. Other gene/disorder must be highly penetrant AND patient’s history must demonstrate no overlap.' The evidence for this variant shows: no reports of this variant in cases with an alternate molecular basis. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
According to VCEP guidelines, the rule for BP6 is: 'Supporting Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.' The evidence for this variant shows: ClinVar entry reports the variant as Likely Benign from a reputable laboratory. Therefore, this criterion is applied at Supporting strength because of the ClinVar benign report per VCEP BP6.
BP7
BP7 (Supporting)
According to VCEP guidelines, the rule for BP7 is: 'Supporting A synonymous (silent) or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice.' The evidence for this variant shows: it is intronic at +17 and splicing tools predict no impact. Therefore, this criterion is applied at Supporting strength because the variant meets BP7 criteria per VCEP.