LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-09-21
Case ID: NM_002439.5_c.1360C_T_20260921_225650
Framework: ACMG/AMP 2015
Variant classification summary

NM_002439.5:c.1360C>T

MSH3  · NP_002430.3:p.(Arg454Ter)  · NM_002439.5
GRCh37: chr5:80021291 C>T  ·  GRCh38: chr5:80725472 C>T
Gene: MSH3 Transcript: NM_002439.5
Final call
Likely Pathogenic
PVS1 very strong PM2 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
MSH3
Transcript
NM_002439.5
Protein
NP_002430.3:p.(Arg454Ter)
gnomAD AF
1.2399240670501338e-05 (v4.1)
ClinVar
Pathogenic
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Likely Pathogenic: PVS1 very strong is met because p.Arg454Ter is an NMD-predicted exon 9 of 24 nonsense removing about 60% of MSH3, a gene where loss of function causes disease.
2
Likely Pathogenic: PM2 supporting is met because gnomAD v2.1 (2.79e-05) and v4.1 (1.24e-05) frequencies are below the 0.0001 cutoff with zero homozygotes.
3
PS3 and PS4 not met: no functional assay and no case-control enrichment exist for this allele.
4
PP5 not met: ClinVar variation 644460 has eight laboratory submissions but zero expert-panel submissions.
5
BA1, BS1, BS2 and BP6 not met: the highest population frequency (about 0.13% in a Korean sub-cohort) is far below the 5% and 1% thresholds, no homozygote is observed, and no expert panel has classified the variant.
6
Final combination: PVS1 (very strong) plus one supporting criterion (PM2) reaches the Likely Pathogenic rule, while PVS1 alone would not have reached Pathogenic.
Final determination: Under the generic ACMG/AMP 2015 rules, one very strong criterion (PVS1) combined with one supporting criterion (PM2) yields Likely Pathogenic, since the criteria combination does not reach any Pathogenic rule.
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 Met Met at very strong: nonsense stop at codon 454 of 1137 in exon 9 of 24, NMD-predicted, deleting about 60% of MSH3 including its DNA-recognition and dimerization domains.
pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment generic_acmg_combination_rules PMID:27476653 PMID:37402566 PMID:28528517 PMID:25741868 clinvar spliceai oncokb
PS1 N/A PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_002439.5:c.1360C>T in MSH3 is a nonsense substitution introducing a premature stop codon predicted to produce NP_002430.3:p.(Arg454Ter). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1'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
PS2 Not assessed Not assessed: no parental or trio testing exists in the case evidence, so de novo status of c.1360C>T cannot be established.
clinvar PMID:25741868 PMID:27476653 PMID:37402566
PS3 Not met Not met: no functional assay of p.Arg454Ter exists - the case's MSH3 functional data (HEK293T/western blot, EMAST) characterise other loss-of-function alleles, not codon 454.
oncokb clinvar PMID:27476653 PMID:28528517 PMID:10706084 PMID:37402566 PMID:25741868
PS4 Not met Not met: no case-control enrichment data exist for this variant, and no odds ratio is reported (gnomAD v4.1 AF 1.24e-05, 20/1,613,002 alleles).
clinvar gnomad_v2 gnomad_v4 PMID:25741868 PMID:27476653 PMID:37402566 PMID:28528517
PM1 N/A PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_002439.5:c.1360C>T in MSH3 is a nonsense substitution introducing a premature stop codon predicted to produce NP_002430.3:p.(Arg454Ter). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1'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
PM2 Met Met at Supporting: gnomAD v2.1 and v4.1 frequencies (0.0000279, 0.0000124) sit below the 0.0001 threshold with zero homozygotes.
gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868 PMID:28528517
PM3 Not assessed Not assessed: no proband genotype or phase data exist, so c.1360C>T cannot be shown in trans with a pathogenic MSH3 allele.
clinvar gnomad_v2 gnomad_v4 PMID:25741868 PMID:27476653 PMID:28528517 PMID:37402566
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.1360C>T in MSH3 is a nonsense substitution introducing a premature stop codon predicted to produce NP_002430.3:p.(Arg454Ter). 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 N/A PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_002439.5:c.1360C>T in MSH3 is a nonsense substitution introducing a premature stop codon predicted to produce NP_002430.3:p.(Arg454Ter). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5'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
PM6 Not assessed Not assessed: no parental genotypes are available, so c.1360C>T cannot be assumed de novo at any strength.
clinvar PMID:25741868 PMID:27476653 PMID:28528517
PP1 Not assessed Not assessed: no pedigree, affected relatives or family genotypes are reported, so co-segregation of c.1360C>T cannot be evaluated.
clinvar PMID:27476653 PMID:37402566 PMID:24493721 PMID:25394175
PP2 N/A PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_002439.5:c.1360C>T in MSH3 is a nonsense substitution introducing a premature stop codon predicted to produce NP_002430.3:p.(Arg454Ter). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2'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
PP3 N/A Not applicable: p.Arg454Ter is a nonsense truncating variant, so neither the REVEL missense path nor the SpliceAI splice path for PP3 applies.
clinvar
PP4 Not assessed Not assessed: no proband phenotype, HPO terms, or family history was provided, so phenotype specificity for MSH3-associated polyposis cannot be evaluated.
PMID:25741868 PMID:27476653 PMID:37402566 PMID:28528517 clinvar
PP5 Not met Not met: ClinVar variation 644460 has zero expert-panel submissions, all 8 being single-submitter laboratories, so the exact-variant expert-panel requirement is unmet.
clinvar PMID:25741868
BA1 Not met Not met: highest gnomAD allele frequency of 0.13 percent (East Asian Korean subset) remains far below the 0.05 BA1 stand-alone threshold.
gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868
BS1 Not met Not met: gnomAD v2.1 allele frequency 0.0000279 is roughly 360-fold below the 0.01 BS1 strong threshold.
gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868 PMID:27476653
BS2 Not met Not met: zero homozygotes in gnomAD (v2.1 7/251,176; v4.1 20/1,613,002) means no healthy homozygous adult supports this recessive variant.
gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868 PMID:27476653
BS3 Not met Not met: no functional assay reports normal MSH3 function for p.Arg454Ter - the case's MSH3 assays cover other alleles and show loss, not preservation, of function.
clinvar oncokb PMID:27476653 PMID:28528517 PMID:10706084 PMID:37402566 PMID:25741868
BS4 Not assessed Not assessed: no family segregation data exist, so non-segregation of c.1360C>T in affected relatives cannot be documented.
clinvar PMID:25741868 PMID:27476653
BP1 N/A BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_002439.5:c.1360C>T in MSH3 is a nonsense substitution introducing a premature stop codon predicted to produce NP_002430.3:p.(Arg454Ter). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1'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
BP2 Not assessed Not assessed: no phase data exist in any source, so c.1360C>T cannot be shown in cis with a pathogenic variant.
clinvar gnomad_v2 gnomad_v4 PMID:25741868 PMID:27476653 PMID:28528517 PMID:37402566
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.1360C>T in MSH3 is a nonsense substitution introducing a premature stop codon predicted to produce NP_002430.3:p.(Arg454Ter). 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 N/A Not applicable: p.Arg454Ter is a nonsense variant, outside the missense/splice-region scope BP4 was calibrated for; its SpliceAI 0.004 was not evaluated.
clinvar
BP5 Not assessed Not assessed: no proband-level data on co-occurring variants or phenotype was provided, so an alternate molecular basis for disease cannot be evaluated.
PMID:25741868 clinvar
BP6 Not met Not met: ClinVar variation 644460 has zero expert-panel submissions, and all 8 laboratory submissions classify the variant Pathogenic or Likely pathogenic.
clinvar PMID:25741868
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.1360C>T in MSH3 is a nonsense substitution introducing a premature stop codon predicted to produce NP_002430.3:p.(Arg454Ter). 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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