PMS2 c.90G>T, p.Gln30His
NM_000535.7:c.90G>T
Variant of Uncertain Significance (VUS)
This legacy system is being phased out as Project HERA V3 is rolled out.
ACMG/AMP Criteria Applied
PM2
BP4
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_000535.3 | Alternative | 15 exons | Reverse |
| NM_000535.5 | Alternative | 15 exons | Reverse |
Variant Details
HGVS Notation
NM_000535.7:c.90G>T
Protein Change
Q30H
Location
Exon 2
(Exon 2 of 15)
5'Exon Structure (15 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 30 in gene PMS2
Variant interpretation based on transcript NM_000535.7
Genome Browser
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HGVS InputNM_000535:c.90G>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
Unknown
Publications (0)
No publication details.
Clinical Statement
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
No evidence of other pathogenic variants at position 30 in gene PMS2
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 3.06
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 Nonsense/frameshift variant introducing Premature Termination Codon (PTC) ≤ codon 798 in PMS2..." The evidence for this variant shows: NM_000535.7:c.90G>T is a missense (Q30H) change, not a null variant. Therefore, this criterion is not applied because the variant does not introduce a stop codon or frameshift.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Strong A predicted missense substitution that encodes the same amino acid change with a different underlying nucleotide change previously established by this VCEP as Pathogenic..." The evidence for this variant shows: there is no previously established pathogenic variant encoding Q30H. Therefore, this criterion is not applied because the amino acid change is not established as pathogenic by another nucleotide change.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 (Very Strong) is: "≥ 4 de novo points..." and lower tiers for fewer points. The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied because de novo status has not been demonstrated.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 (Strong) is: "Calibrated functional assays with functional odds for Pathogenicity >18.7..." The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied because functional assay data are lacking.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "The prevalence of the variant in affected individuals is significantly increased compared with controls." The evidence for this variant shows: no case‐control or cohort data are available. Therefore, this criterion is not applied because there is no evidence of increased prevalence in affected individuals.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or critical and well‐established functional domain without benign variation." The evidence for this variant shows: Q30 is not reported as a mutational hotspot or critical domain. Therefore, this criterion is not applied because the residue is not known to lie in a critical functional region.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset." The evidence for this variant shows: NM_000535.7:c.90G>T is not present in gnomAD or other population databases. Therefore, this criterion is applied at Supporting strength because the variant is absent from controls.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 (Supporting) is: "0.5 points for detection in trans with a pathogenic variant in a recessive gene." The evidence for this variant shows: no trans phasing data with a pathogenic PMS2 variant. Therefore, this criterion is not applied because there is no evidence of trans occurrence in a recessive context.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions in non-repetitive region or stop-loss variants." The evidence for this variant shows: Q30H is a missense change with no length change. Therefore, this criterion is not applied because there is no alteration of protein length.
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 was classified as Pathogenic by this VCEP." The evidence for this variant shows: no other pathogenic missense variant at residue 30. Therefore, this criterion is not applied because no pathogenic variant at the same residue exists.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity." The evidence for this variant shows: no de novo data or parental testing. Therefore, this criterion is not applied because unconfirmed de novo status is not documented.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co‐segregation with disease in multiple affected family members." The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied because familial co‐segregation has not been evaluated.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation and where missense variants are a common mechanism of disease." The evidence for this variant shows: insufficient information on benign missense rate in PMS2. Therefore, this criterion is not applied due to lack of gene‐specific constraint data.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 (Supporting) is: "Missense variant with MAPP/PP2 Prior P score >0.68 & ≤0.81 OR predicted splice defect with SpliceAI delta score ≥0.2." The evidence for this variant shows: SpliceAI delta score 0.08 and low CADD, indicating no predicted impact. Therefore, this criterion is not applied because computational evidence does not support a deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 (Strong/Moderate/Supporting) is: "Number of independent CRC/Endometrial MSI-H tumors with consistent loss of PMS2 expression." The evidence for this variant shows: no tumor IHC or MSI data. Therefore, this criterion is not applied because no tumor phenotype data are available.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic." The evidence for this variant shows: no entries in ClinVar or other databases. Therefore, this criterion is not applied because no reputable pathogenic assertion exists.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone GnomAD v4 Grpmax filtering allele frequency ≥0.0028 (0.28%)." The evidence for this variant shows: allele frequency is 0% in gnomAD. Therefore, this criterion is not applied because the variant frequency is below the BA1 threshold.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 (Strong) is: "GnomAD v4 Grpmax filtering allele frequency ≥0.0001 and <0.001." The evidence for this variant shows: allele frequency is 0% in gnomAD. Therefore, this criterion is not applied because the variant frequency does not meet BS1 thresholds.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 (Strong) is: "Co‐occurrence in trans with a known pathogenic PMS2 variant in a patient without CMMRD features." The evidence for this variant shows: no co‐occurrence data. Therefore, this criterion is not applied because no evidence of trans occurrence with a pathogenic variant is available.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 (Strong) is: "Calibrated functional assays with functional odds for Pathogenicity ≤0.05 OR synonymous/intronic with no mRNA aberration." The evidence for this variant shows: no functional assay data. Therefore, this criterion is not applied because no experimental evidence of benign functional effect exists.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 (Strong) is: "Lack of co‐segregation with disease in pedigree(s) (Bayes LR <0.05)." The evidence for this variant shows: no segregation studies. Therefore, this criterion is not applied because segregation analysis has not been performed.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene for which primarily truncating variants cause disease." The evidence for this variant shows: PMS2 disease mechanism includes both missense and truncating variants. Therefore, this criterion is not applied because missense variants can be pathogenic in PMS2.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant for any disorder." The evidence for this variant shows: no phasing data. Therefore, this criterion is not applied because there is no evidence of cis/trans configuration with a pathogenic variant.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In‐frame deletions/insertions in repetitive region without a known function." The evidence for this variant shows: Q30H is a missense change. Therefore, this criterion is not applied because it does not involve an in‐frame indel.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting 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: SpliceAI maximum delta score 0.08 and in silico predictors indicate no impact. Therefore, this criterion is applied at Supporting strength because computational evidence predicts no effect.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 (Supporting) is: "Tumor data inconsistent with Lynch syndrome for multiple tumors or BRAF V600E/MLH1 methylation patterns." The evidence for this variant shows: no tumor molecular data. Therefore, this criterion is not applied because tumor context is unavailable.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign." The evidence for this variant shows: no such reports exist. Therefore, this criterion is not applied because no reputable benign assertion is available.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting A synonymous or intronic variant at or beyond –21/+7." The evidence for this variant shows: Q30H is missense. Therefore, this criterion is not applied because the variant is not synonymous or intronic.