Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000251.2 | RefSeq Select | 3226 nt | 126–2930 |
| NM_000251.1 | Alternative | 3145 nt | 69–2873 |
| NM_000251.3 | MANE Select | 3115 nt | 37–2841 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open"This variant has been reported in ClinVar as Uncertain significance (2 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 | -221 bp |
| Donor Loss (DL) | 0.06 | -9 bp |
| Acceptor Gain (AG) | 0.0 | 474 bp |
| Donor Gain (DG) | 0.0 | 4 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: a missense substitution (G68V) with no introduction of a PTC or canonical splice‐site alteration. Therefore, this criterion is not applied because the variant is not a null variant as defined by PVS1.
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: no other nucleotide change at codon 68 previously classified as Pathogenic. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: "De novo evidence with ≥1 confirmed de novo points…". The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: "Calibrated functional assays with functional odds for Pathogenicity >18.7 (Strong)…". The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion 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 data. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: "Located in a mutational hotspot or functional domain without benign variation…". The evidence for this variant shows: codon 68 is not defined as a VCEP‐specified hotspot. Therefore, this criterion 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: not present in gnomAD (MAF = 0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from population controls.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: "Evidence of pathogenic variant in trans for a recessive disorder…". The evidence for this variant shows: no trans observations or recessive context reported. Therefore, this criterion 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...". The evidence for this variant shows: a single amino acid change without alteration of protein length. Therefore, this criterion 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 as Pathogenic…". The evidence for this variant shows: no different missense variant at codon 68 classified as Pathogenic. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines, the rule for PM6 is: "Unconfirmed de novo occurrence…". The evidence for this variant shows: no de novo information. Therefore, this criterion is not applied.
PP1 (Not Applied)
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. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation…". The evidence for this variant shows: MSH2 has known pathogenic and benign missense variations; gene‐specific rate not met. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Moderate if HCI prior probability for pathogenicity >0.81…". The evidence for this variant shows: no HCI prior probability data provided. Therefore, this criterion cannot be evaluated and is not applied.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 is: "Tumor phenotype consistent with MMR defect…". The evidence for this variant shows: no tumor MSI or protein expression data. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports as pathogenic…". The evidence for this variant shows: ClinVar reports VUS only. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone if allele frequency ≥0.1% in gnomAD…". The evidence for this variant shows: not observed in gnomAD. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong if allele frequency 0.01–0.1% in gnomAD…". The evidence for this variant shows: absent from controls. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Co‐occurrence in trans with a known pathogenic variant in older unaffected individual…". The evidence for this variant shows: no co‐occurrence data. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Strong if calibrated functional assays show benign function…". The evidence for this variant shows: no functional assays. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "Lack of co‐segregation with disease…". The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in gene where only truncating variants cause disease…". The evidence for this variant shows: MSH2 has known pathogenic missense variants. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a dominant disorder…". The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In‐frame indel in repetitive region without known function…". The evidence for this variant shows: single amino acid substitution, not an indel. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple computational lines support a benign effect…". The evidence for this variant shows: computational tools predict deleterious effect. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 is: "Tumors inconsistent with gene defect…". The evidence for this variant shows: no tumor data or co‐occurrence with another etiology. Therefore, this criterion 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 benign assertions. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Synonymous or intronic variant at non‐critical positions…". The evidence for this variant shows: missense change. Therefore, this criterion is not applied.