Variant classification summary

NM_000251.3:c.403C>G

MSH2 · NP_000242.1:p.(Leu135Val) · NM_000251.3

GRCh37: chr2:47637269 C>G · GRCh38: chr2:47410130 C>G

Gene: MSH2 Transcript: NM_000251.3

Final call

VUS

Variant details

Gene

MSH2

Transcript

NM_000251.3

Protein

NP_000242.1:p.(Leu135Val)

gnomAD AF

5.638417575009542e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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.

3

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.

4

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.

5

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 determination: Because no adjudicated criteria met an applicable strength tier, none of the MSH2 VCEP Version 2.0 pathogenic, likely pathogenic, benign, or likely benign combination rules was satisfied, leaving the classification as VUS.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Not applicable: c.403C>G is a missense SNV (p.Leu135Val), not one of the VCEP-defined premature-termination, splice-disrupting, or genomic-alteration PVS1 paths.	cspec vcep_pvs1_decisiontree_mmr vcep_vcep_pilot_variants_mmr
PS1	Not met	Not met: no different-nucleotide p.Leu135Val variant is established as Pathogenic by this VCEP.	cspec vcep_hci_priors_msh2
PS2	Not assessed	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	Not assessed: no variant-specific calibrated functional result or functional odds are reported for MSH2 c.403C>G (p.Leu135Val).	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart
PS4	N/A	Not applicable: the MSH2 VCEP excludes PS4 proband-counting classification because tumor IHC evidence is evaluated through PP4.	cspec
PM1	N/A	Not applicable: the MSH2 VCEP recognizes no usable mutational hotspot or domain-based PM1 path.	cspec vcep_mmr_functional_domains
PM2	Not met	Not met: gnomAD v4.1 total allele frequency is 5.63842e-05, exceeding the VCEP PM2 cutoff of 0.00002.	cspec gnomad_v4 vcep_vcep_pilot_variants_mmr
PM3	Not assessed	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.	cspec
PM4	N/A	Not applicable: the MSH2 VCEP explicitly excludes PM4, and c.403C>G changes one amino acid without changing protein length.	cspec vcep_pvs1_decisiontree_mmr vcep_vcep_pilot_variants_mmr
PM5	Not assessed	Not assessed: no qualifying different missense variant at residue 135 has a governing VCEP Pathogenic or Likely Pathogenic classification.	cspec pm5_candidates vcep_hci_priors_msh2
PM6	N/A	Not applicable: the MSH2 VCEP explicitly marks PM6 Not Applicable, so no PM6 evidence is evaluated.	cspec
PP1	Not assessed	Not assessed: no informative meioses or combined Bayes likelihood ratio is documented, so the VCEP PP1 thresholds cannot be evaluated.
PP2	N/A	Not applicable: the MSH2 VCEP explicitly excludes PP2 for missense variants in this gene.	cspec
PP3	Not met	Not met: HCI prior probability is 0.135, below the VCEP PP3 Supporting threshold of >0.68 and the Moderate threshold of >0.81.	vcep_hci_priors_msh2
PP4	Not assessed	Not assessed: no eligible MSI-H tumor or MSH2-consistent MMR-protein loss is documented to meet the VCEP PP4 rule.	cspec vcep_table_for_cmmrd_diagnosis vcep_vcep_pilot_variants_mmr
PP5	N/A	Not applicable: the MSH2 VCEP prohibits PP5 use regardless of reported pathogenic classifications.	cspec
BA1	Not met	Not met: gnomAD v4.1 joint Grpmax filtering allele frequency is 0.00070274, below the VCEP BA1 threshold of 0.001.	cspec gnomad_v4 vcep_vcep_pilot_variants_mmr
BS1	Not assessed	Not assessed: gnomAD v4.1 Grpmax filtering allele frequency is 0.00070274 within range, but founder-pathogenic-variant exclusion is not documented.	cspec gnomad_v4
BS2	Not assessed	Not assessed: no eligible in-trans co-occurrence, cancer-age, CMMRD, or parent/offspring phase evidence is available.	cspec
BS3	Not assessed	Not assessed: no variant-specific proficient-function result or calibrated benign functional odds are reported for MSH2 c.403C>G (p.Leu135Val).	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart
BS4	Not assessed	Not assessed: no non-segregating relatives or combined Bayes likelihood ratio is documented, so the VCEP BS4 thresholds cannot be evaluated.
BP1	N/A	Not applicable: the MSH2 VCEP explicitly excludes BP1 for missense variants in this gene.	cspec
BP2	N/A	Not applicable: the VCEP states that BP2 is not used and that BS2 is used instead.	cspec
BP3	N/A	Not applicable: the MSH2 VCEP explicitly excludes BP3, and c.403C>G is a missense SNV rather than an in-frame indel in a repeat region.	cspec vcep_pvs1_decisiontree_mmr vcep_vcep_pilot_variants_mmr
BP4	Not met	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.	vcep_hci_priors_msh2
BP5	Not assessed	Not assessed: no qualifying MSS, MMR-protein, BRAF V600E, or MLH1-methylation tumor result is documented for BP5.	cspec
BP6	N/A	Not applicable: the MSH2 VCEP prohibits BP6 use regardless of reported benign classifications.	cspec
BP7	N/A	Not applicable: c.403C>G is a missense variant producing p.L135V, whereas VCEP BP7 covers only synonymous or intronic variants.

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