LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-08-11
Case ID: NM_002439.5_c.2041C_T_20260811_162123
Framework: ACMG/AMP 2015
Variant classification summary

NM_002439.5:c.2041C>T

MSH3  · NP_002430.3:p.(Pro681Ser)  · NM_002439.5
GRCh37: chr5:80063896 C>T  ·  GRCh38: chr5:80768077 C>T
Gene: MSH3 Transcript: NM_002439.5
Final call
VUS
BP1 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
MSH3
Transcript
NM_002439.5
Protein
NP_002430.3:p.(Pro681Ser)
gnomAD AF
0.001743809908608001 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
BP1 (Supporting): MSH3 germline disease is driven by truncating variants, and no pathogenic missense in MSH3 is established, so this missense change is consistent with a benign role.
2
Classification: VUS — a single supporting benign criterion does not reach the Benign (BA1 alone, or 2 BS) or Likely Benign (1 BS + 1 BP, or 2 BP) combination thresholds under generic ACMG/AMP 2015.
Final determination: Under the generic ACMG/AMP 2015 fallback combination rules, the only met criterion is a single supporting benign criterion (BP1), which does not reach the Benign (BA1 alone, or 2 strong benign) or Likely Benign (1 strong benign + 1 supporting benign, or 2 supporting benign) thresholds and no pathogenic/likely-pathogenic combination is present, so the variant is classified as Variant of Uncertain Significance.
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: this is a missense substitution, so no null-variant mechanism such as nonsense-mediated decay is triggered.
pvs1_generic_framework generic_acmg_combination_rules
PS1 Not met Not met: the same change, p.(Pro681Ser), appears in the literature and ClinVar, but no source establishes it as pathogenic.
clinvar PMID:11470537 PMID:32634176
PS2 Not assessed Not assessed: no proband-parent trio or parental-testing data exists for this variant in any source.
clinvar PMID:11470537 PMID:32634176 PMID:28944238 PMID:20981092
PS3 Not assessed Not assessed: no functional study of this variant exists; a ClinVar submitter states none have been performed.
clinvar oncokb PMID:32634176 PMID:11470537 PMID:28944238
PS4 Not met Not met: the single carrier in 199 cases (0.5%) does not exceed the 0.229% population frequency, so no enrichment is demonstrated.
PMID:32634176 gnomad_v2 gnomad_v4 PMID:11470537 PMID:28944238
PM1 Not met Not met: despite a conserved ATPase-region location, 7 gnomAD v4.1 homozygotes show benign variation at this exact residue.
gnomad_v2 gnomad_v4 PMID:11470537 generic_acmg_combination_rules
PM2 Not met Not met: the highest population allele frequency (0.229% in gnomAD v4.1) exceeds the 0.1% PM2 threshold.
gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868 PMID:32634176
PM3 Not assessed Not assessed: no source provides phase or second-allele data showing the variant in trans with a pathogenic MSH3 variant.
PMID:11470537 PMID:32634176 PMID:28944238 PMID:20981092 PMID:25741868 clinvar gnomad_v4
PM4 N/A Not applicable: this missense substitution does not alter protein length, so the length-change premise does not apply.
pvs1_generic_framework generic_acmg_combination_rules
PM5 Not assessed Not assessed: no alternate missense change at codon 681 with an established pathogenic classification was identified.
pm5_candidates clinvar PMID:32634176
PM6 Not assessed Not assessed: no de novo or assumed-de-novo occurrence is reported in ClinVar or the variant-bearing publications.
clinvar PMID:11470537 PMID:32634176
PP1 Not assessed Not assessed: no affected relatives of any carrier have been genotyped, so co-segregation cannot be evaluated.
clinvar PMID:11470537 PMID:32634176 PMID:28944238
PP2 Not met Not met: MSH3 is missense-tolerant (this variant has 7 gnomAD v4.1 homozygotes), and disease is loss-of-function mediated, not missense-driven.
gnomad_v4 pvs1_gene_context PMID:11470537 PMID:32634176
PP3 Not met Not met: REVEL 0.496 falls below the 0.773 PP3 supporting threshold, and SpliceAI 0.03 predicts no splice impact.
spliceai revel bayesdel PMID:25741868
PP4 Not assessed Not assessed: no documented proband phenotype or family history is available to evaluate.
PMID:32634176 clinvar
PP5 Not met Not met: ClinVar VCV000656200 has zero expert-panel submissions, and PP5 requires an exact-variant expert-panel pathogenic classification.
clinvar
BA1 Not met Not met: the highest allele frequency (0.229%) is far below the 5% BA1 stand-alone threshold.
gnomad_v2 gnomad_v4 PMID:25741868
BS1 Not met Not met: the highest allele frequency (0.229%) falls below the 0.3% BS1 operating threshold. Flagged for human review: prevalence and penetrance assumptions materially affect this call.
gnomad_v2 gnomad_v4 PMID:25741868 PMID:32634176
BS2 Not met Not met: although 7 gnomAD v4.1 homozygotes exist, MSH3 polyposis is adult-onset and incompletely penetrant, failing BS2's early-age full-penetrance requirement.
gnomad_v2 gnomad_v4 PMID:25741868
BS3 Not assessed Not assessed: no functional assay of this variant exists; population frequency and in silico scores cannot substitute.
clinvar oncokb PMID:32634176 PMID:11470537 PMID:28944238
BS4 Not assessed Not assessed: no affected family member of any carrier has been genotyped, so lack of segregation cannot be shown.
clinvar PMID:11470537 PMID:32634176
BP1 Met Met (supporting): MSH3 disease is truncation-mediated with no established pathogenic missense, so this missense favors a benign role. Flagged for human review: the pathogenic MSH3 missense spectrum is small and no VCEP governs this gene.
pvs1_gene_context PMID:11470537 PMID:32634176 generic_acmg_combination_rules
BP2 Not assessed Not assessed: no phase data exists to show the variant in cis or trans with a pathogenic variant.
PMID:11470537 PMID:32634176 PMID:28944238 PMID:25741868 clinvar
BP3 N/A Not applicable: this missense substitution is not an in-frame indel in a repetitive region.
pvs1_generic_framework generic_acmg_combination_rules
BP4 Not met Not met: REVEL 0.496 exceeds the 0.016 BP4 threshold, leaving SpliceAI 0.03 as the only benign-direction line.
spliceai revel bayesdel PMID:25741868
BP5 Not assessed Not assessed: no co-occurring pathogenic variant in another gene is documented, and no proband genotype data exists.
clinvar PMID:32634176
BP6 Not met Not met: ClinVar has zero expert-panel submissions; the six likely-benign assertions are ordinary laboratory calls, which never trigger BP6.
clinvar
BP7 N/A Not applicable: BP7 applies only to synonymous variants, and this is a missense substitution.
generic_acmg_combination_rules
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