Variant classification summary

NM_002439.5:c.495A>G

MSH3 · NP_002430.3:p.(Lys165=) · NM_002439.5

GRCh37: chr5:79961098 A>G · GRCh38: chr5:80665279 A>G

Gene: MSH3 Transcript: NM_002439.5

Final call

VUS

PM2 supporting

Variant details

Gene

MSH3

Transcript

NM_002439.5

Protein

NP_002430.3:p.(Lys165=)

gnomAD AF

4.7711165280151284e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: maximum observed gnomAD population allele frequency is 6.27113e-05, below 0.0001.

2

VUS: one supporting criterion does not satisfy a generic ACMG/AMP pathogenic or benign combination rule.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting criterion alone does not meet any pathogenic, likely pathogenic, likely benign, or benign combination threshold, 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.495A>G in MSH3 is a synonymous (silent) substitution predicted to produce NP_002430.3:p.(Lys165=). 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	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.495A>G in MSH3 is a synonymous (silent) substitution predicted to produce NP_002430.3:p.(Lys165=). 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 confirmed proband genotype with both parental genotypes demonstrating a de novo NM_002439.5:c.495A>G event.
PS3	Not assessed	Not assessed: no validated functional assay for the exact synonymous variant was identified; SpliceAI max delta 0.003 is computational, not assay evidence.	spliceai
PS4	Not assessed	Not assessed: no exact-variant case-control counts, enrichment statistic, or odds ratio were available to evaluate PS4.
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.495A>G in MSH3 is a synonymous (silent) substitution predicted to produce NP_002430.3:p.(Lys165=). 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 v4.1 maximum population AF is 6.27113e-05, below the PM2 threshold of 0.0001.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband genotype or phase data establish NM_002439.5:c.495A>G in trans with a pathogenic MSH3 allele.
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.495A>G in MSH3 is a synonymous (silent) substitution predicted to produce NP_002430.3:p.(Lys165=). 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.495A>G in MSH3 is a synonymous (silent) substitution predicted to produce NP_002430.3:p.(Lys165=). 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 assumed-de-novo case report supplies a proband phenotype or parental testing context for NM_002439.5:c.495A>G.
PP1	Not assessed	Not assessed: zero informative meioses or phenotype-consistent affected relatives are documented for NM_002439.5:c.495A>G.
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.495A>G in MSH3 is a synonymous (silent) substitution predicted to produce NP_002430.3:p.(Lys165=). 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: the variant is synonymous, outside PP3's missense or intronic/splice-region scope.
PP4	Not assessed	Not assessed: no specific patient phenotype or phenotype-to-MSH3 disease match was documented for this exact variant.
PP5	Not met	Not met: ClinVar lists three single-submitter Likely benign laboratory assertions and zero expert-panel Pathogenic/Likely pathogenic submissions.	clinvar
BA1	Not met	Not met: maximum observed allele frequency is 6.27113e-05, far below the generic BA1 threshold of 0.05.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: maximum observed allele frequency is 6.27113e-05, below the generic BS1 threshold of 0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports 0 homozygotes, but carrier health and penetrance are not established for BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no validated benign functional assay for the exact synonymous variant was identified; SpliceAI max delta 0.003 is computational, not assay evidence.	spliceai
BS4	Not assessed	Not assessed: no tested unaffected relatives or informative non-segregation events are documented for NM_002439.5:c.495A>G.
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.495A>G in MSH3 is a synonymous (silent) substitution predicted to produce NP_002430.3:p.(Lys165=). 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 genotype or phase data show NM_002439.5:c.495A>G in cis or trans with a pathogenic variant under an applicable inheritance model.
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.495A>G in MSH3 is a synonymous (silent) substitution predicted to produce NP_002430.3:p.(Lys165=). 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: the variant is synonymous, outside BP4's missense or intronic/splice-region scope.
BP5	Not assessed	Not assessed: no exact-variant affected case with a confirmed alternative molecular explanation was documented.
BP6	Not met	Not met: ClinVar has three single-submitter Likely benign laboratory assertions but zero exact-variant expert-panel Benign or Likely benign submissions.	clinvar
BP7	Not assessed	Not assessed: synonymous variant with SpliceAI max delta 0.003 versus <=0.1, but conservation status is unavailable.	spliceai PMID:25741868

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