Variant classification summary

NM_002439.5:c.131C>G

MSH3 · NP_002430.3:p.(Ala44Gly) · NM_002439.5

GRCh37: chr5:79950677 C>G · GRCh38: chr5:80654858 C>G

Gene: MSH3 Transcript: NM_002439.5

Final call

VUS

PM2 supporting BP4 moderate

Variant details

Gene

MSH3

Transcript

NM_002439.5

Protein

NP_002430.3:p.(Ala44Gly)

gnomAD AF

7.488925751045641e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: gnomAD v4.1 shows very low allele frequency and zero homozygotes.

2

BP4 moderate: REVEL 0.138 is below the calibrated moderate benign computational threshold.

3

VUS: PM2 supporting plus BP4 moderate does not meet a generic ACMG/AMP final classification threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting PM2 criterion plus one moderate benign BP4 criterion does not meet a defined benign, likely benign, likely pathogenic, or pathogenic combination, so the call is 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	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.131C>G in MSH3 is a missense substitution predicted to produce NP_002430.3:p.(Ala44Gly). 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 assessed	Not assessed: no validated pathogenic MSH3 comparator producing the same amino-acid change, p.Ala44Gly, was identified.	clinvar
PS2	Not assessed	Not assessed: no parental genotypes or confirmed de novo observation are documented for the affected proband.
PS3	Not assessed	Not assessed: no variant-specific validated functional assay with appropriate controls was identified for MSH3 p.(Ala44Gly).
PS4	Not assessed	Not assessed: no exact-variant case-control counts, enrichment statistic, or statistically supported affected-case series were available.
PM1	Not assessed	Not assessed: no authoritative MSH3 domain table was retrieved, and the A44 hotspot query found no statistically significant hotspot.
PM2	Met	Met at supporting: gnomAD v4.1 total AF is 7.48893e-06, below the generic PM2 threshold of 0.0001, with zero homozygotes.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	Not assessed	Not assessed: no affected individual, second pathogenic allele, phase, or biallelic MSH3 observation is documented for c.131C>G.
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.131C>G in MSH3 is a missense substitution predicted to produce NP_002430.3:p.(Ala44Gly). 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 assessed	Not assessed: zero eligible pathogenic missense comparators were identified at MSH3 residue 44.	pm5_candidates clinvar
PM6	Not assessed	Not assessed: no clinical report or family-history evidence supports a presumed de novo event without parental testing.
PP1	Not assessed	Not assessed: no informative affected relatives, familial variant testing, or meiosis count is documented for segregation analysis.
PP2	Not assessed	Not assessed: MSH3 loss-of-function support does not establish the gene-level missense enrichment required for PP2.	PMID:25741868
PP3	Not met	Not met: missense REVEL score 0.138 is below the >=0.644 supporting PP3 threshold.	revel
PP4	Not assessed	Not assessed: no patient phenotype, family history, or disease-specific clinical presentation was provided to evaluate phenotype specificity.
PP5	Not met	Not met: ClinVar shows 0 expert-panel submissions for the exact variant, with available laboratory assertions classified as uncertain significance or likely benign.	clinvar
BA1	Not met	Not met: gnomAD v4.1 maximum reported subgroup AF is 1.02135e-05, far below the generic BA1 threshold of 0.05.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: gnomAD v4.1 maximum reported subgroup AF is 1.02135e-05, below the generic BS1 threshold of 0.01.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD v2.1 and v4.1 report zero homozygotes for the variant, with no qualifying healthy-individual genotype observation.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific validated assay demonstrated preserved MSH3 function for p.(Ala44Gly).
BS4	Not assessed	Not assessed: no informative unaffected relatives with documented negative familial testing are available to evaluate non-segregation.
BP1	Not assessed	Not assessed: MSH3 loss-of-function support alone does not prove that pathogenic variants are primarily truncating.	PMID:25741868
BP2	Not assessed	Not assessed: no individual-level cis/trans phase or pathogenic comparator allele is documented for the MSH3 c.131C>G variant.
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.131C>G in MSH3 is a missense substitution predicted to produce NP_002430.3:p.(Ala44Gly). 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 moderate strength: missense REVEL score 0.138 is below the <=0.183 moderate BP4 threshold.	revel
BP5	Not assessed	Not assessed: no case-level alternative molecular diagnosis was documented for a patient carrying the exact variant.	clinvar
BP6	Not met	Not met: the only Likely benign ClinVar assertion is an ordinary laboratory submission, and exact-variant expert-panel submissions number 0.	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.131C>G in MSH3 is a missense substitution predicted to produce NP_002430.3:p.(Ala44Gly). 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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