Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000251.3 | MANE Select | 3115 nt | 37–2841 |
| NM_000251.2 | RefSeq Select | 3226 nt | 126–2930 |
| NM_000251.1 | Alternative | 3145 nt | 69–2873 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenThis missense variant replaces valine with isoleucine at codon 150 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been observed in a cohort of individuals affected with prostate cancer (PMID: 31874108). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 150 of the MSH2 protein (p.Val150Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 582751). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
"This variant has been reported in ClinVar as Uncertain significance (4 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 | 117 bp |
| Donor Loss (DL) | 0.02 | 43 bp |
| Acceptor Gain (AG) | 0.02 | 16 bp |
| Donor Gain (DG) | 0.0 | -7 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 Premature Termination Codon (PTC) ≤ codon 891 in MSH2...". The evidence for this variant shows: NM_000251.3:c.448G>A is a missense change (p.V150I), not a null or splice-site variant. Therefore, this criterion is not applied because the variant type does not meet PVS1 requirements.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "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: p.V150I has not been previously established as pathogenic via any nucleotide change. Therefore, PS1 is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: "Very Strong: ≥4 de novo points; Strong: 2–3 de novo points; Moderate: 1 de novo point; Supporting: 0.5 de novo points.". The evidence for this variant shows: de novo status has not been assessed (no parental testing). Therefore, PS2 is not applied due to lack of de novo evidence.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: "Strong: Calibrated functional assays with functional odds for Pathogenicity >18.7; Moderate: assays with odds >4.3 ≤18.7; Supporting: odds >2.08 ≤4.3.". The evidence for this variant shows: no functional studies have been performed on MSH2 p.V150I. 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 with controls.". The evidence for this variant shows: no case–control or segregation prevalence data are available. Therefore, PS4 is not applied.
PM1 (Not Applied)
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: p.V150I is not located in a known critical functional domain or hotspot. Therefore, PM1 is not applied.
PM2 (Supporting)
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_000251.3:c.448G>A is not found in gnomAD or other population databases. Therefore, PM2 is applied at Supporting strength.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: "Points for variants detected in trans with a pathogenic variant in recessive disorders.". The evidence for this variant shows: no data on in trans occurrence with a pathogenic MSH2 variant. 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 in a non-repeat region or stop‐loss variants.". The evidence for this variant shows: p.V150I is a missense substitution, not an in‐frame indel. Therefore, PM4 is not applied.
PM5 (Not Applied)
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.". The evidence for this variant shows: no other pathogenic missense changes at codon 150 in MSH2. Therefore, PM5 is not applied.
PM6 (Not Applied)
According to VCEP guidelines, the rule for PM6 is: "Supporting: Unconfirmed de novo occurrence.". The evidence for this variant shows: de novo status is unassessed. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "Supporting/Moderate/Strong co‐segregation evidence based on Bayes LR thresholds.". The evidence for this variant shows: no family segregation data. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense is a common mechanism.". The evidence for this variant shows: MSH2 has both truncating and missense pathogenic variants. Therefore, PP2 is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Moderate: HCI prior probability >0.81; Supporting: HCI >0.68≤0.81 or SpliceAI ≥0.2.". The evidence for this variant shows: mixed in silico predictions and SpliceAI delta score 0.02. Therefore, PP3 is not applied.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 is: "Tumor phenotype with MSI‐H and/or loss of MMR protein expression consistent with variant location.". 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: "Reputable source reports variant as pathogenic.". The evidence for this variant shows: ClinVar entries all list Uncertain Significance. Therefore, PP5 is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone: gnomAD v4 Grpmax filtering allele frequency ≥0.001 (0.1%).". The evidence for this variant shows: allele frequency = 0%. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong: allele frequency ≥0.0001 and <0.001 in gnomAD v4.". The evidence for this variant shows: allele frequency = 0%. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Strong: observed in trans with a known pathogenic variant in a healthy individual.". The evidence for this variant shows: no such observations. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Strong: calibrated functional assays with odds ≤0.05; Supporting: odds >0.05≤0.48.". 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: "Lack of segregation in affected members.". The evidence for this variant shows: no segregation data. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only truncating variants cause disease.". The evidence for this variant shows: MSH2 pathogenic variants include missense changes. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant in a dominant disorder.". The evidence for this variant shows: no such observations. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In‐frame indels in a repetitive region.". The evidence for this variant shows: p.V150I is a missense variant. Therefore, BP3 is not applied.
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting: Missense variant with HCI‐prior probability <0.11 or SpliceAI delta score ≤0.1.". The evidence for this variant shows: mixed in silico predictions overall benign and SpliceAI 0.02. Therefore, BP4 is applied at Supporting strength.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 is: "Tumors inconsistent with Lynch syndrome phenotype.". 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: "Reputable source reports variant as benign.". The evidence for this variant shows: no such reports. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Synonymous or intronic variant with no splicing impact.". The evidence for this variant shows: p.V150I is a missense change. Therefore, BP7 is not applied.