PMS2 c.1362G>A, p.Leu454=
NM_000535.7:c.1362G>A
Likely Benign
Synonymous variant c.1362G>A (p.L454=) in PMS2 is absent from population databases (PM2_sup), computationally predicted to have no splice impact (BP4), reported as benign in ClinVar (BP6), and meets BP7 for synonymous no-splice-change. No evidence of pathogenicity is present, supporting a Likely Benign classification.
ACMG/AMP Criteria Applied
PM2
BP4
BP6
BP7
Genetic Information
Gene & Transcript Details
Gene
PMS2
Transcript
NM_000535.7
MANE Select
Total Exons
15
Strand
Reverse (−)
Reference Sequence
NC_000007.13
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000535.6 | Alternative | 15 exons | Reverse |
| NM_000535.4 | Alternative | 15 exons | Reverse |
| NM_000535.5 | Alternative | 15 exons | Reverse |
| NM_000535.3 | Alternative | 15 exons | Reverse |
Variant Details
HGVS Notation
NM_000535.7:c.1362G>A
Protein Change
L454=
Location
Exon 11
(Exon 11 of 15)
5'Exon Structure (15 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_000535.7
Genome Browser
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HGVS InputNM_000535:c.1362G>A
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 2 submitter reviews in ClinVar
Submitter Breakdown
1 LB
1 B
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) and as 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: -0.50
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines for PVS1: "Very Strong Nonsense/frameshift variant introducing Premature Termination Codon (PTC) ≤ codon 798 in PMS2…". The evidence for this variant shows it is a synonymous substitution (no PTC). Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines for PS1: "Strong: A predicted missense substitution that encodes the same amino acid change with a different underlying nucleotide change previously established as Pathogenic…". The evidence for this variant shows no amino acid change. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG for PS2: requires confirmed de novo occurrence. No de novo data are available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG for PS3: "Functional studies supportive of a damaging effect on the gene or gene product." No functional assay data are available. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG for PS4: requires case–control or family-based statistical evidence of pathogenicity. No such data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG for PM1: requires variant in a mutational hot spot or well-established functional domain without benign variation. This variant is synonymous outside known hotspots. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines for PM2: "Supporting Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset." The evidence for this variant shows absence from population databases (MAF=0%). Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines for PM3: requires observed in trans with a pathogenic variant in a recessive disorder. No such data are available. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG for PM4: pertains to protein length changes. This is a synonymous variant. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines for PM5: requires missense change at a residue with a different pathogenic missense. This is synonymous. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG for PM6: unconfirmed de novo. No de novo evidence. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG for PP1: requires co-segregation with disease. No segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG for PP2: pertains to missense variants in genes with low benign variation. This is synonymous. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines for PP3: supporting for non-canonical splice or high prior missense. SpliceAI score is 0.05 (no impact) and variant is synonymous. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG for PP4: requires specific phenotype or family history. No phenotype data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG for PP5: requires reputable source reporting pathogenic. No such report. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines for BA1: "Stand Alone: GnomAD v4 grpmax filtering allele frequency ≥0.0028." Variant MAF=0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines for BS1: "Strong: GnomAD v4 grpmax filtering allele frequency ≥0.0001 and <0.001." Variant MAF=0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines for BS2: requires co-occurrence in trans with a known pathogenic variant. No such data. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines for BS3: "Strong: Synonymous substitutions with no associated mRNA aberration as determined by laboratory assays." No laboratory mRNA assay data are available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG for BS4: requires lack of segregation with disease. No segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG for BP1: pertains to missense in genes where only truncating variants cause disease. This is synonymous. Therefore, not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG for BP2: observed in trans with a pathogenic variant in a dominant disorder. No such data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG for BP3: in-frame indels in repetitive regions. Not applicable to synonymous SNV. Therefore, not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines for BP4: "Supporting: For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score ≤0.1." SpliceAI max delta=0.05. Therefore, this criterion is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG for BP5: requires variant found in a case with an alternate molecular cause. No such case data. Therefore, not applied.
BP6
BP6 (Supporting)
According to standard ACMG for BP6: "Supporting: Reputable source recently reports variant as benign but evidence not available to laboratory." ClinVar reports Likely benign/Benign. Therefore, this criterion is applied at Supporting strength.
BP7
BP7 (Supporting)
According to standard ACMG for BP7: "Supporting: A synonymous variant at or beyond -21/+7 exonic with no predicted splice impact." SpliceAI delta ≤0.1. Therefore, this criterion is applied at Supporting strength.