Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000535.6 | Alternative | 5156 nt | 88–2676 |
| NM_000535.4 | Alternative | 2836 nt | 88–2676 |
| NM_000535.7 | MANE Select | 5093 nt | 31–2619 |
| NM_000535.3 | Alternative | 2820 nt | 57–2645 |
| NM_000535.5 | Alternative | 2851 nt | 88–2676 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenThe PMS2 c.779C>T (p.Ser260Phe) variant has been reported in the published literature in an individual with breast cancer (PMID: 35449176 (2022)). The frequency of this variant in the general population (Genome Aggregation Database, http://gnomad.broadinstitute.org) is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
"This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 73 bp |
| Donor Loss (DL) | 0.0 | 266 bp |
| Acceptor Gain (AG) | 0.0 | -140 bp |
| Donor Gain (DG) | 0.01 | 18 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule for PVS1 is: "Very Strong: Nonsense/frameshift variant introducing a premature termination codon or splice site variants expected to undergo NMD." The evidence for this variant shows it is a missense change (p.Ser260Phe). Therefore, this criterion is not applied because the variant is not a null variant.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "Strong: A predicted missense substitution that encodes the same amino acid change as a previously established pathogenic variant." The evidence for this variant shows no previously established pathogenic variant results in p.Ser260Phe. Therefore, PS1 is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: "Very Strong/Strong/Moderate/Supporting based on de novo points." The evidence for this variant shows no data on de novo occurrence or parental testing. Therefore, PS2 is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: "Strong: Calibrated functional assays with functional odds for Pathogenicity >18.7." The evidence for this variant shows no functional studies are available. Therefore, PS3 is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "The prevalence of the variant in affected individuals is significantly increased compared to controls." The evidence for this variant shows no case-control or patient cohort data. Therefore, PS4 is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or well‐studied functional domain without benign variation." The evidence for this variant shows no data placing codon 260 in a recognized hotspot or critical domain. Therefore, PM1 is not applied.
PM2 (Not Applied)
According to VCEP guidelines, the rule for PM2 is: "Supporting: Absent or extremely rare (<1 in 50,000 alleles) in gnomAD." The evidence for this variant shows a maximum population MAF of 0.0177% (1 in ~5,650 alleles), exceeding the 0.002% threshold. Therefore, PM2 is not applied.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: "Supporting: Observed in trans with a pathogenic variant in a recessive disorder." The evidence for this variant shows no observation of the variant in trans in a recessive context. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants." The evidence for this variant shows it is a missense change without length alteration. Therefore, PM4 is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: "Moderate: Missense change at an amino acid residue where a different missense change has been classified as pathogenic by this VCEP." The evidence for this variant shows no other pathogenic missense variant at codon 260. Therefore, PM5 is not applied.
PM6 (Not Applied)
According to VCEP guidelines, the rule for PM6 is: "Supporting: De novo occurrence without confirmation of parental identity." The evidence for this variant shows no de novo or parental data. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: "Supporting: Co-segregation with disease in multiple affected family members." The evidence for this variant shows no segregation data. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Supporting: Missense variant in a gene with a low rate of benign missense variation." The evidence for this variant shows PMS2 does not have a well‐established low benign missense variation metric. Therefore, PP2 is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Moderate: Missense variant with HCI prior >0.81 or SpliceAI delta ≥0.2." The evidence for this variant shows SpliceAI delta=0.01 and no high HCI prior. Therefore, PP3 is not applied.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 is: "Strong: ≥3 independent CRC/Endometrial MSI-H tumors or consistent loss of MMR protein." The evidence for this variant shows no tumor or IHC data. Therefore, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Supporting: Reputable source reports variant as pathogenic." The evidence for this variant shows ClinVar reports it as VUS. Therefore, PP5 is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone: gnomAD v4 MAF ≥0.28%." The evidence for this variant shows MAF=0.0177%, below threshold. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong: gnomAD v4 MAF ≥0.01% and <0.1%." The evidence for this variant shows a maximum MAF of 0.157% in South Asians, exceeding 0.1%. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Strong: Observed in trans with a pathogenic variant in a healthy adult." The evidence for this variant shows no such co-occurrence data. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Strong: Calibrated functional assays showing no functional impact (odds ≤0.05)." The evidence for this variant shows no functional assays. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: "Strong: Lack of co-segregation in affected family members." The evidence for this variant shows no segregation data. Therefore, BS4 is not applied.
BP1 (Supporting)
According to standard ACMG guidelines, the rule for BP1 is: "Supporting: Missense variant in a gene where truncating variants are the known mechanism of disease." The evidence for this variant shows PMS2 disease mechanism is loss-of-function and this is a missense change. Therefore, BP1 is applied at Supporting strength.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Supporting: Observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant." The evidence for this variant shows no such data. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "Supporting: In-frame indel in a repetitive region without known function." The evidence for this variant shows it is a missense change. Therefore, BP3 is not applied.
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting: SpliceAI predicts no impact with delta ≤0.1 or MAPP/PP2 prior <0.11." The evidence for this variant shows SpliceAI delta=0.01 indicating no splicing impact. Therefore, BP4 is applied at Supporting strength.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 is: "Supporting: Tumor data showing inconsistent loss of MMR protein on tumors with MSS or BRAF/MLH1 methylation patterns." The evidence for this variant shows no tumor data. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Supporting: Reputable source reports variant as benign." The evidence for this variant shows ClinVar reports it as VUS. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: "Supporting: Synonymous or intronic variant without splicing impact." The evidence for this variant shows it is missense. Therefore, BP7 is not applied.