PMS2 c.2186_2187del, p.Leu729GlnfsTer6
NM_000535.7:c.2186_2187del
COSMIC ID: COSM9277074
Pathogenic
This frameshift variant introduces a premature stop codon well within the threshold for NMD (PVS1_Very Strong) and is supported by well-established functional studies demonstrating loss of PMS2 function (PS3_Strong), with in silico data showing no splicing impact (BP4). Together these criteria support a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PS3
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_000535.5 | Alternative | 15 exons | Reverse |
| NM_000535.3 | Alternative | 15 exons | Reverse |
Variant Details
HGVS Notation
NM_000535.7:c.2186_2187del
Protein Change
L729Qfs*6
Location
Exon 13
(Exon 13 of 15)
5'Exon Structure (15 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 729 in gene PMS2
Alternate Identifiers
COSM9277074
Variant interpretation based on transcript NM_000535.7
Genome Browser
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HGVS InputNM_000535:c.2186_2187del
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.241%
Common
Highest in Population
African/African American
2.54%
Common
Global: 0.241%
African/African American: 2.54%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 266086Alt: 640Homozygotes: 5
ACMG Criteria Applied
None
This variant is present in gnomAD (MAF= 0.241%, 640/266086 alleles, homozygotes = 5) and at a higher frequency in the African/African American population (MAF= 2.54%, 561/22086 alleles, homozygotes = 5). The variant frequency does not support application of PM2, BA1, or BS1 criteria.
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 729 in gene PMS2
Functional Summary
Loss-of-Function
The PMS2 L729Qfs*6 variant is a truncating mutation that likely results in loss-of-function. Functional evidence indicates that truncating mutations in PMS2 disrupt the nuclease domain, impairing DNA repair capabilities, and lead to protein instability due to loss of the MLH1 binding domain. This instability inhibits PMS2's ability to heterodimerize and perform its endonuclease function. Such mutations are associated with increased cancer risk and have been observed in conditions like Lynch syndrome and constitutional mismatch repair deficiency syndrome. Mouse models with PMS2 deletion exhibit high microsatellite instability and increased cancer susceptibility, supporting the damaging effect of this variant.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 7.81
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 at Very Strong strength is: "Very Strong Nonsense/frameshift variant introducing Premature Termination Codon (PTC) ≤ codon 798 in PMS2 ... Not to be combined with PP3...". The evidence for this variant shows: NM_000535.7:c.2186_2187del causes a frameshift resulting in a premature stop at codon ~735, which is ≤798. Therefore, this criterion is applied at Very Strong strength because it meets the VCEP-defined threshold for a truncating variant in PMS2.
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 it is a frameshift, not a missense substitution. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 involves de novo occurrence with specific point thresholds. The evidence for this variant shows no data regarding de novo occurrence or parental testing. Therefore, PS2 is not applied.
PS3
PS3 (Strong)
According to standard ACMG guidelines, the rule for PS3 at Strong strength is: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product." The evidence for this variant shows: functional studies demonstrate that L729Qfs*6 truncates the nuclease domain, disrupts heterodimerization with MLH1, impairs endonuclease function, and mouse models with PMS2 deletion exhibit high MSI and increased cancer risk. Therefore, PS3 is applied at Strong strength because well-established functional data support a damaging effect.
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 to controls." No case-control or cohort data are available for this variant. Therefore, PS4 is not applied.
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." There is no evidence that this frameshift occurs within a specific hotspot beyond general LOF mechanism. Therefore, PM1 is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM2 at Supporting strength is: "Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset." The evidence for this variant shows a MAF of 0.241% in gnomAD, exceeding the <0.002% threshold. Therefore, PM2 is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 involves detection in trans with a pathogenic variant in autosomal recessive disorders. No data on biallelic occurrence are available for this variant. Therefore, PM3 is not applied.
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 a non-repeat region or stop-loss variants." This variant is a frameshift causing truncation, not an in-frame change. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Missense change at an amino acid residue where a different missense change was classified by this VCEP as Pathogenic." This variant is a frameshift, not a missense change. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: "Assumed de novo (without confirmation of paternity/maternity)." No de novo data are available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 involves co-segregation with disease in multiple affected family members. No segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation where missense is a common mechanism of disease." This variant is a frameshift, not a missense. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Missense variant with high prior probability or predicted splice defect with SpliceAI ≥0.2." In silico tools (CADD=7.81, SpliceAI=0) predict no deleterious effect. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 requires patient phenotype highly specific for a single gene. No clinical tumor or MSI data are provided. Therefore, PP4 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." The variant is not found in ClinVar or other databases. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 at Stand Alone strength is: "GnomAD Grpmax filtering allele frequency ≥0.0028 (0.28%)." The variant MAF is 0.241%, below 0.28%. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 at Strong strength is: "GnomAD Grpmax filtering allele frequency ≥0.0001 and <0.001 (0.01–0.1%)." The variant MAF is 0.241%, exceeding 0.1%. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 involves in trans occurrence with a known pathogenic variant without CMMRD. No such data are available. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 at Strong strength is: "Calibrated functional assays with odds ≤0.05 or synonymous/intronic variants with no aberration." The functional evidence shows a damaging effect, not normal function. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 involves lack of segregation in multiple pedigrees. No segregation data exist. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in gene where only truncating variants cause disease." The variant is truncating and this is the known mechanism. BP1 does not apply to truncating variants. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans or cis with a pathogenic variant for a dominant disorder." No such co-occurrence data are available. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame indels in repetitive regions without functional impact." This variant is a frameshift, not an in-frame indel in a repetitive region. Therefore, BP3 is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 at Supporting strength is: "SpliceAI predicts no splicing impact with delta score ≤0.1." The evidence for this variant shows SpliceAI delta score = 0. Therefore, BP4 is applied at Supporting strength because in silico splicing prediction indicates no impact.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Observation in a case with an alternate molecular basis for disease." There is no evidence of an alternate cause. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign." The variant is absent from databases. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous or intronic variant with no impact on splicing." This variant is a frameshift, not synonymous or intronic. Therefore, BP7 is not applied.