PMS2 c.852A>G, p.Ser284=
NM_000535.7:c.852A>G
Population Frequency
0.00159%
Low Frequency
ClinVar Classification
Uncertain Significance (VUS)
0 publications
REVEL Score
N/A
Not Available
COSMIC Recurrence
0 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
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.852A>G
Protein Change
S284=
Location
Exon 8
(Exon 8 of 15)
5'
Exon Structure (15 total)
3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_000535.7
Clinical Evidence
Global Frequency
0.00159%
Rare
Highest in Population
Admixed American
0.0116%
Low Frequency
Global: 0.00159%
Admixed American: 0.0116%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
Allele Information
Total: 251434
Alt: 4
Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00159%, 4/251434 alleles, homozygotes = 0) and at a higher frequency in the Admixed American population (MAF= 0.0116%, 4/34592 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Uncertain Significance (VUS)
Based on 4 submitter reviews in ClinVar
Submitter Breakdown
Pathogenic
Likely Pathogenic
VUS
Likely Benign
Benign
Publications
0 publications
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratories) and as Likely benign (3 clinical laboratories) and as Likely Benign (1 clinical laboratories).
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
Functional Studies
Computational Evidence
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria
VCEP Guidelines
PVS1
PVS1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PVS1 is: 'PVS1 not applicable or not evaluated'. The evidence for this variant, being a synonymous change (S284=) with no indication of affecting splicing or causing a null effect, supports that it does not meet PVS1. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS1 requires a predicted missense change identical to a known pathogenic change. The evidence for this variant shows a synonymous change with no amino acid alteration. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PS2 requires de novo occurrence confirmed in the patient. The evidence does not indicate any de novo status. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PS3 is based on calibrated functional assays demonstrating a deleterious impact. The provided evidence states that no functional studies have been performed for this variant. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PS4 requires an increased prevalence in affected individuals compared to controls. The evidence does not support an excess in cases; hence, this criterion is not applied.
PM1
PM1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PM1 applies to variants in a mutational hotspot or critical functional domain. This variant is synonymous and does not affect a known hotspot region. Therefore, this criterion is not applied.
PM2
PM2 (Supporting)
Strength Modified
According to standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium'. The evidence for this variant shows a minor allele frequency of 0.00159% (extremely rare) in gnomAD and other databases, supporting application of PM2 at a Supporting strength. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PM3 is used for recessive disorders when the variant is observed in trans with a pathogenic variant. The evidence for this variant does not include such data. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length changes due to in-frame insertions/deletions. Given that the variant is synonymous with no protein length change, this criterion is not applied.
PM5
PM5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PM5 applies when a different missense change at the same amino acid residue has been reported as pathogenic. The evidence for this variant shows no missense change; thus, PM5 is not applicable.
PM6
PM6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PM6 involves assumed de novo status without confirmation. The evidence does not support a de novo occurrence. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PP1 requires co-segregation with disease in multiple affected family members. There is no segregation data provided for this variant. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PP2 is used for genes with a low rate of benign missense variation, but this variant is synonymous. The evidence does not support this criterion for a synonymous change. Therefore, it is not applied.
PP3
PP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PP3 requires multiple lines of computational evidence supporting a deleterious effect. The evidence for this variant shows conflicting in silico predictions and essentially no predicted functional effect. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PP4 requires a highly specific phenotype associated with the gene. Since the clinical phenotype consistent with PMS2 has not been provided in relation to this variant, this criterion is not applied.
PP5
PP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PP5 involves a reputable source reporting the variant as pathogenic. Although ClinVar submissions exist, the reports are conflicting and include Likely Benign calls; therefore, PP5 is not applied.
BA1
BA1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BA1 requires an allele frequency that is too high for the disorder (>5%). The evidence shows a very low allele frequency, so BA1 is not applied.
BS1
BS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BS1 is met when allele frequency is greater than expected for the disorder. The evidence shows a frequency much lower than the threshold; therefore, BS1 is not applied.
BS2
BS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BS2 requires observation of the variant in healthy individuals with conditions that have full penetrance. The evidence does not include such observations for this variant. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BS3 necessitates well-established functional studies showing no impact of the variant on gene function. The evidence indicates that functional studies have not been conducted. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BS4 is based on lack of segregation with disease. There is no segregation data provided, so this criterion is not applied.
BP1
BP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP1 applies when missense variants are less likely to affect gene function in genes where truncating variants predominate. Since this variant is synonymous and there is no missense change, BP1 is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP2 involves observation in trans with a pathogenic variant for a dominant disorder. There is no such evidence for this variant, so BP2 is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP3 is used for in-frame deletions or insertions in repetitive regions with no functional impact. The evidence for this synonymous variant does not meet that scenario. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: 'Missense variant with MAPP/PP2 Prior P score <0.11 OR for intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score <= 0.1'. The evidence for this variant shows that multiple lines of computational prediction, including SpliceAI (with a maximum score for acceptor gain of 0.12 which is interpreted in context as not significant), suggest no impact on splicing or function. Therefore, BP4 is applied at Supporting strength.
BP5
BP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP5 requires that the variant is observed in tumors or individuals with features inconsistent with the gene’s disease spectrum. The evidence does not support this scenario; hence, BP5 is not applied.
BP6
BP6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP6 involves reputable source reporting of a benign impact. While some ClinVar submissions exist, the evidence is conflicting; therefore, BP6 is not applied.
BP7
BP7 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP7 applies to synonymous variants located at or beyond the -21/+7 positions with no predicted splicing impact. Although this variant is synonymous, the original assessment did not apply BP7, likely due to insufficient positional context. Therefore, this criterion is not applied.