LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-09-29
Case ID: NM_002439.5_c.1522A_G_20260929_231606
Framework: ACMG/AMP 2015
Variant classification summary

NM_002439.5:c.1522A>G

MSH3  · NP_002430.3:p.(Lys508Glu)  · NM_002439.5
GRCh37: chr5:80024738 A>G  ·  GRCh38: chr5:80728919 A>G
Gene: MSH3 Transcript: NM_002439.5
Final call
Likely Benign
BP1 supporting BP4 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
MSH3
Transcript
NM_002439.5
Protein
NP_002430.3:p.(Lys508Glu)
gnomAD AF
0.00024308901646928087 (v4.1)
ClinVar
Conflicting classifications of pathogenicity
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Likely Benign: BP1 (supporting) - p.(Lys508Glu) is a missense change in MSH3, whose established pathogenic variants are truncating (frameshift, nonsense, splice) against 1170 missense variants of uncertain significance.
2
Likely Benign: BP4 (supporting) - REVEL 0.191 sits in the benign range (<=0.29) for this missense variant.
Final determination: Under the generic ACMG/AMP 2015 combination rules, two supporting benign criteria (BP1 + BP4) with no pathogenic-direction evidence classify the variant as Likely Benign.
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 PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_002439.5:c.1522A>G in MSH3 is a missense substitution predicted to produce NP_002430.3:p.(Lys508Glu). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
pvs1_generic_framework generic_acmg_combination_rules
PS1 Not met Not met: p.Lys508Glu is not established as pathogenic - ClinVar shows 5 Likely benign and 1 VUS submission and no pathogenic assertion.
clinvar
PS2 Not assessed Not assessed: no parental-testing data exist, so the confirmed de novo PS2 requires (PMID:25741868) is undeterminable; gnomAD v2.1 shows 106 alleles and v4.1 two homozygotes.
generic_acmg_combination_rules PMID:25741868 clinvar gnomad_v2 gnomad_v4
PS3 Not met Not met: no assay has tested p.(Lys508Glu), and OncoKB reports no variant-specific functional evidence for this change.
generic_acmg_combination_rules PMID:25741868 PMID:28944238 clinvar oncokb
PS4 Not met Not met: no case-control enrichment exists, as the variant is absent from the 1231-case CRC cohort and present in gnomAD v4.1 at 392/1,612,578 alleles.
clinvar PMID:28944238 PMID:25741868 gnomad_v4 generic_acmg_combination_rules
PM1 Not met Not met: residue 508 lies in MSH3 MutS domain II but is no hotspot and is not free of benign variation (gnomAD popmax AF 0.44%, 2 homozygotes).
gnomad_v4 gnomad_v2 clinvar oncokb
PM2 Not met Not met: total allele frequency 0.024-0.038% in gnomAD v4.1/v2.1 exceeds the 0.01% PM2 rarity threshold, with the African/African American popmax at 0.44%.
gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules PMID:25741868
PM3 Not met Not met: no pathogenic variant was observed in trans with MSH3 c.1522A>G, and no phase-resolved proband data supports an in-trans configuration.
PMID:25741868 clinvar pvs1_gene_context gnomad_v4
PM4 N/A PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_002439.5:c.1522A>G in MSH3 is a missense substitution predicted to produce NP_002430.3:p.(Lys508Glu). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
pvs1_generic_framework generic_acmg_combination_rules
PM5 Not met Not met: the only other codon-508 missense variant, p.Lys508Arg, has conflicting ClinVar classifications and is not established pathogenic.
clinvar pm5_candidates
PM6 Not assessed Not assessed: no parental testing or de novo observation is documented, so PM6's assumed-de-novo premise (PMID:25741868) cannot be evaluated; the variant recurs in gnomAD (106 v2.1 alleles).
generic_acmg_combination_rules PMID:25741868 clinvar gnomad_v2 gnomad_v4
PP1 Not assessed Not assessed: no pedigree or relative genotypes exist and no paper reports this variant in a family, so PP1 co-segregation (PMID:25741868) cannot be evaluated.
generic_acmg_combination_rules PMID:25741868 PMID:28492532 PMID:28944238 pvs1_gene_context
PP2 Not met Not met: MSH3 shows no missense constraint (gnomAD oe_mis 1.08, mis_z -1.29) and its established pathogenic variants are truncating, not missense.
gnomad_v4 clinvar pvs1_gene_context
PP3 Not met Not met: REVEL 0.191 for this missense variant is below the >=0.644 PP3 supporting threshold.
revel
PP4 Not assessed Not assessed: no proband phenotype or family history was recorded for this case, so PP4's requirement for a highly specific single-gene disease phenotype cannot be tested.
clinvar PMID:25741868 generic_acmg_combination_rules final_classification_framework
PP5 N/A Not applicable: ClinVar holds seven submissions for this variant with zero from expert panels and conflicting classifications, so the expert-panel pathogenic assertion PP5 requires does not exist.
clinvar PMID:25741868 PMID:24493721 PMID:24929052 PMID:25394175 generic_acmg_combination_rules
BA1 Not met Not met: the highest frequency at usable sample size is 0.44% (gnomAD v4.1 African/African American), roughly tenfold below the 5% stand-alone benign threshold.
gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules PMID:25741868
BS1 Not met Not met: the highest frequency at usable sample size is 0.44% (gnomAD v4.1 African/African American), about 2.3-fold below the generic 1% BS1 threshold.
gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules PMID:25741868
BS2 N/A Not applicable: MSH3 disease is adult-onset with unestablished penetrance, so BS2's requirement of full penetrance at an early age is unmet, and its 2 gnomAD homozygotes are uninformative.
gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules PMID:25741868
BS3 Not met Not met: no functional assay of p.(Lys508Glu) exists, so preserved MSH3 function has never been experimentally demonstrated.
generic_acmg_combination_rules PMID:25741868 PMID:28944238 clinvar oncokb
BS4 Not assessed Not assessed: no pedigree or relative genotypes exist to demonstrate non-segregation, and absence of family data is not BS4 evidence (PMID:25741868).
generic_acmg_combination_rules PMID:25741868 PMID:28492532 clinvar
BP1 Met Met at supporting: MSH3 disease is caused by truncating variants - ClinVar MSH3 P/LP records are frameshift/nonsense/splice versus 1170 missense VUS.
clinvar pvs1_gene_context PMID:25741868
BP2 Not met Not met: neither a cis nor a trans pathogenic variant was observed with MSH3 c.1522A>G, and no phase-resolved partner allele is reported anywhere.
PMID:25741868 PMID:28492532 clinvar PMID:28944238
BP3 N/A BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_002439.5:c.1522A>G in MSH3 is a missense substitution predicted to produce NP_002430.3:p.(Lys508Glu). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
pvs1_generic_framework generic_acmg_combination_rules
BP4 Met Met at supporting strength: REVEL 0.191 is within the <=0.29 BP4 supporting threshold but above the <=0.183 moderate cut-off.
revel
BP5 Not assessed Not assessed: no case carrying this variant was reported anywhere in the evidence, so the alternate-molecular-basis observation BP5 requires could not be evaluated.
clinvar PMID:25741868 PMID:28944238 generic_acmg_combination_rules final_classification_framework
BP6 N/A Not applicable: no expert-panel ClinVar assertion exists for this variant (seven laboratory submissions, conflicting classifications), so BP6's expert-panel benign precondition is unmet.
clinvar PMID:25741868 generic_acmg_combination_rules
BP7 N/A BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_002439.5:c.1522A>G in MSH3 is a missense substitution predicted to produce NP_002430.3:p.(Lys508Glu). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
generic_acmg_combination_rules
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