NM_000251.3:c.403C>G is a missense SNV (NP_000242.1:p.(Leu135Val)), so it does not enter the VCEP-defined PVS1 null-variant paths. The MSH2 VCEP explicitly marks PM4 and BP3 as Not Applicable; the missense substitution also produces neither a protein-length change nor an in-frame indel in a repeat region. For the requested codon, residue, and domain criteria, the governing MSH2 VCEP makes PM1, PP2, and BP1 not applicable; PS1 is not met because no qualifying VCEP Pathogenic same-amino-acid comparator was found; PM5 remains not assessed because no qualifying VCEP-classified alternate missense comparator at residue 135 is available. Among the requested criteria, PM6 is not applicable under the VCEP specification; PS2, PP1, and BS4 cannot be assessed because case-specific de novo, segregation, and non-segregation data are not documented. PS4, PP5, and BP6 are not applicable under the MSH2 VCEP rules. PP4 and BP5 are not assessed because the required variant-specific tumor phenotype, MSI/IHC, tumor-genome, BRAF V600E, and MLH1-methylation evidence is not available.
Final classification
VUS
MSH2
c.403C>G
p.Leu135Val
missense · exon 3
Gene context
NCBI Gene ↗
OncoKB ↗
MSH2 is a tumor suppressor gene that encodes a key protein in the DNA mismatch repair system, which finds and fixes errors made during DNA replication. The MSH2 protein pairs with MSH6 or MSH3 to form complexes that recognize mismatched base pairs and trigger their repair. Inherited mutations in MSH2 cause Lynch syndrome (hereditary nonpolyposis colorectal cancer), predisposing to colorectal, endometrial, ovarian, and other cancers, and biallelic mutations cause constitutional mismatch repair deficiency. Loss of MSH2 function increases the mutation rate and drives tumor development, particularly in colorectal and endometrial cancers, and mismatch-repair-deficient tumors respond particularly well to immune checkpoint inhibitor therapies.
This variant
MSH2 encodes a core DNA mismatch-repair protein, and inherited MSH2 variants are associated with Lynch syndrome and constitutional mismatch repair deficiency.
VUS: no adjudicated pathogenic or benign-strength criteria were applied under the MSH2 VCEP Version 2.0 combination rules.
Classification rationale
VUS
MSH2 c.403C>G
missense · exon 3
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_000251.3 · variants mapped to exon structure
MSH2
NM_000251.3
Fetching transcript structure from UCSC…
Applied criteria · 0 applied · 16 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 0
No criteria were applied for this variant.
Assessed · not applied
· 5 not met · 11 not assessed
Pathogenic
PS1
Not met: no different-nucleotide p.Leu135Val variant is established as Pathogenic by this VCEP.
PS2
Not assessed: no proband-level de novo observation or parental testing is documented, so the VCEP's de novo-point thresholds cannot be applied.
PS3
Not assessed: no variant-specific calibrated functional result or functional odds are reported for MSH2 c.403C>G (p.Leu135Val).
PM2
Not met: gnomAD v4.1 total allele frequency is 5.63842e-05, exceeding the VCEP PM2 cutoff of 0.00002.
PM3
Not assessed: no documented CMMRD-phenotype proband carried this variant with a second pathogenic/likely pathogenic MSH2 variant, so no PM3 points could be assigned.
PM5
Not assessed: no qualifying different missense variant at residue 135 has a governing VCEP Pathogenic or Likely Pathogenic classification.
PP1
Not assessed: no informative meioses or combined Bayes likelihood ratio is documented, so the VCEP PP1 thresholds cannot be evaluated.
PP3
Not met: HCI prior probability is 0.135, below the VCEP PP3 Supporting threshold of >0.68 and the Moderate threshold of >0.81.
PP4
Not assessed: no eligible MSI-H tumor or MSH2-consistent MMR-protein loss is documented to meet the VCEP PP4 rule.
Benign
BA1
Not met: gnomAD v4.1 joint Grpmax filtering allele frequency is 0.00070274, below the VCEP BA1 threshold of 0.001.
BS1
Not assessed: gnomAD v4.1 Grpmax filtering allele frequency is 0.00070274 within range, but founder-pathogenic-variant exclusion is not documented.
BS2
Not assessed: no eligible in-trans co-occurrence, cancer-age, CMMRD, or parent/offspring phase evidence is available.
BS3
Not assessed: no variant-specific proficient-function result or calibrated benign functional odds are reported for MSH2 c.403C>G (p.Leu135Val).
BS4
Not assessed: no non-segregating relatives or combined Bayes likelihood ratio is documented, so the VCEP BS4 thresholds cannot be evaluated.
BP4
Not met: HCI prior probability is 0.1350, above the VCEP BP4 missense threshold of <0.11; its SpliceAI alternative does not cover missense variants.
BP5
Not assessed: no qualifying MSS, MMR-protein, BRAF V600E, or MLH1-methylation tumor result is documented for BP5.
N/A · 12
PVS1 · PS4 · PM1 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 5.63842e-05; MAF= 0.00564%, 91/1613928 alleles, homozygotes = 2) and has highest observed frequency in the South Asian population (AF= 0.000856371; MAF= 0.08564%, 78/91082 alleles, homozygotes = 2); grpmax FAF= 0.00070274.
v2.1
This variant is present in gnomAD v2.1 (AF= 9.94779e-05; MAF= 0.00995%, 25/251312 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000489972; MAF= 0.04900%, 15/30614 alleles, homozygotes = 0); grpmax FAF= 0.00030156.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.00010856584518510477, 2/18422 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0056%
· 91 / 1,613,928
2 hom · FAF 0.07%
2 hom · FAF 0.07%
South Asian 78 / 91,082 |
0.086% 2 hom |
Admixed American 1 / 59,992 |
0.0017% |
Remaining individuals 1 / 62,480 |
0.0016% |
European (non-Finnish) 11 / 1,179,926 |
0.00093% |
+ 6 not observed (European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0099%
· 25 / 251,312
0 hom · FAF 0.03%
0 hom · FAF 0.03%
South Asian 15 / 30,614 |
0.049% |
European (non-Finnish) 9 / 113,622 |
0.0079% |
Admixed American 1 / 34,572 |
0.0029% |
+ 5 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)
gnomAD Canada 🇨🇦
0.011%
· 2 / 18,422
0 hom · FAF 0.026%
0 hom · FAF 0.026%
indel · split
South Asian 2 / 1,362 |
0.15% |
+ 8 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, European (non-Finnish), Remaining individuals)
ClinVar
This variant has been reported in ClinVar as Uncertain significance (9 clinical laboratories) and as Benign (3 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Likely Benign (1 clinical laboratory). (ClinVarID = 187103)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.275. BayesDel score = 0.267297. HCI prior probability for pathogenicity = 0.135. MAPP score = 14.17. Custom PP2 score = 0.311.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MSH2, a DNA mismatch repair protein, is frequently mutated in colorectal, small bowel, and endometrial cancers.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
Triaged references · 8 PMIDs not cited in assessment
27363726 ↗
Classification of genetic variants in genes associated with Lynch syndrome using a clinical history weighting algorithm.
CLINVAR