Variant classification summary

NM_002439.5:c.1567G>A

MSH3 · NP_002430.3:p.(Glu523Lys) · NM_002439.5

GRCh37: chr5:80024783 G>A · GRCh38: chr5:80728964 G>A

Gene: MSH3 Transcript: NM_002439.5

Final call

Likely Benign

BS1 strong BP1 supporting BP4 supporting

Variant details

Gene

MSH3

Transcript

NM_002439.5

Protein

NP_002430.3:p.(Glu523Lys)

gnomAD AF

0.0013872000041661567 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Benign: BS1 (strong) is met at 2.67% African/African American gnomAD frequency, about 2.5-fold above the generic 1% threshold, with 7 and 24-25 homozygotes across two gnomAD releases.

2

Likely Benign: BP1 (supporting) is met because MSH3 disease is driven by truncating loss-of-function alleles (ClinVar: 319 frameshift and 161 nonsense versus one missense pathogenic record).

3

Likely Benign: BP4 (supporting) is met because REVEL 0.228 is at or below the 0.29 missense BP4 cutoff, indicating a tolerated amino-acid substitution.

4

Benign drivers: BS1 (strong) plus BP1 and BP4 (supporting) satisfy the generic ACMG/AMP 2015 Likely Benign combination, with no pathogenic criterion met.

Final determination: Under the generic ACMG/AMP 2015 benign combinations, one strong benign criterion (BS1) together with one supporting benign criterion - here two, BP1 and BP4 - classifies 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.1567G>A in MSH3 is a missense substitution predicted to produce NP_002430.3:p.(Glu523Lys). 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: no established pathogenic variant carries p.Glu523Lys, and the only variant with this amino-acid change (ClinVar VCV000780543) is classified Benign/Likely benign by 15 submitters.	clinvar
PS2	Not assessed	Not assessed: no proband, parental testing, or pedigree data were provided, so a confirmed de novo occurrence in an affected patient could not be evaluated.	PMID:25741868 PMID:28492532 PMID:33007869 gnomad_v2 gnomad_v4 gnomad_canada
PS3	Not met	Not met: no functional assay of MSH3 p.(Glu523Lys) exists; the sole paper reporting it gives no functional data.	PMID:25741868 PMID:33007869 PMID:26467025 PMID:28492532 oncokb clinvar pvs1_gene_context generic_acmg_combination_rules
PS4	Not met	Not met: no case-control enrichment exists for c.1567G>A, which is instead common in gnomAD (popmax 2.5% African/African American).	PMID:33007869 gnomad_v2 gnomad_v4
PM1	Not met	Not met: MSH3 E523 is not a significant hotspot (CancerHotspots: no result), lies outside any annotated functional domain, and carries gnomAD v4.1 AF 0.139% with 25 homozygotes.	gnomad_v4 gnomad_v2 clinvar
PM2	Not met	Not met: gnomAD v4.1 allele frequency 0.0013872 (2,131/1,536,188 alleles) is about 14-fold above the 0.0001 PM2 supporting threshold.	gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868
PM3	Not met	Not met: no case pairs this allele in trans with a pathogenic MSH3 variant, and the only reported carrier (tumour NGS, case IBC15) has undetermined phase.	PMID:33007869 clinvar
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.1567G>A in MSH3 is a missense substitution predicted to produce NP_002430.3:p.(Glu523Lys). 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: residue 523 has no established pathogenic missense, only p.Glu523Val as uncertain significance (single submitter) in ClinVar.	pm5_candidates clinvar PMID:33007869
PM6	Not assessed	Not assessed: the record contains no parental or proband data suggesting an assumed de novo occurrence, so PM6 cannot be evaluated.	PMID:25741868 PMID:28492532 PMID:33007869 gnomad_v2 gnomad_v4 gnomad_canada
PP1	Not assessed	Not assessed: no pedigree, affected relatives, or co-segregation data were available for this variant in MSH3.	PMID:25741868 PMID:28492532 PMID:33007869 gnomad_v2 gnomad_v4
PP2	Not met	Not met: MSH3 tolerates missense variation (gnomAD oe_mis 1.083, mis_z -1.295) and ClinVar pathogenic MSH3 records are 480 truncating versus one missense.	gnomad_v4 clinvar pvs1_gene_context
PP3	Not met	Not met: REVEL 0.228 is far below the >=0.644 supporting PP3 threshold for this missense variant.	revel
PP4	Not assessed	Not assessed: no proband phenotype, HPO terms, or family history is available to test phenotype specificity.	clinvar
PP5	Not met	Not met: ClinVar VCV000780543 has zero expert-panel submissions and only 2-star laboratory-level review for c.1567G>A.	clinvar
BA1	Not met	Not met: the highest ancestry-specific frequency, 2.67% in gnomAD v2.1 African/African American, stays below the 5% BA1 stand-alone threshold.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Met	Met (strong): African/African American frequency 2.67% (655/24,526 alleles, gnomAD v2.1) exceeds the 1% generic BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868 PMID:28492532
BS2	Not met	Not met: 24 gnomAD v4.1 homozygotes are not verifiable as unaffected adults for an adult-onset, incompletely penetrant recessive disorder, as BS2 requires.	gnomad_v2 gnomad_v4 PMID:25741868
BS3	Not met	Not met: no functional study shows a non-damaging effect for MSH3 p.(Glu523Lys); no assay of this variant was identified.	PMID:25741868 PMID:33007869 PMID:26467025 PMID:28492532 oncokb clinvar pvs1_gene_context generic_acmg_combination_rules
BS4	Not assessed	Not assessed: no family or segregation data were available to test for non-segregation of this variant with disease.	PMID:25741868 PMID:28492532 PMID:33007869
BP1	Met	Met at supporting: MSH3 disease is driven by truncating loss-of-function alleles, with ClinVar showing 480 frameshift/nonsense versus one missense pathogenic record.	pvs1_gene_context clinvar gnomad_v4
BP2	Not met	Not met: no pathogenic MSH3 variant is documented in cis or in trans with c.1567G>A, and MSH3 disease is recessive rather than fully penetrant dominant.	PMID:33007869 clinvar
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.1567G>A in MSH3 is a missense substitution predicted to produce NP_002430.3:p.(Glu523Lys). 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 0.228 is at or below the <=0.29 supporting BP4 threshold for this missense variant.	revel
BP5	Not met	Not met: no case is documented in which c.1567G>A was found alongside an established alternate molecular basis for disease.	PMID:33007869
BP6	Not met	Not met: the Benign/Likely benign ClinVar label is an aggregate of non-expert laboratory submissions, not an expert-panel assertion.	clinvar
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.1567G>A in MSH3 is a missense substitution predicted to produce NP_002430.3:p.(Glu523Lys). 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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