NM_002439.5:c.316C>G

MSH3 · NP_002430.3:p.(Gln106Glu) · NM_002439.5

GRCh37: chr5:79952308 C>G · GRCh38: chr5:80656489 C>G

Gene: MSH3 Transcript: NM_002439.5

Final call

VUS

BP1 supporting BP4 moderate

Variant details

Gene

MSH3

Transcript

NM_002439.5

Protein

NP_002430.3:p.(Gln106Glu)

gnomAD AF

0.00014869704216800288 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

BP1 supporting: MSH3 loss of function is established, without an established pathogenic missense mechanism at residue 106.

BP4 moderate: REVEL 0.176 meets the moderate benign threshold, with concordant SpliceAI max delta 0.001.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting benign criterion and one moderate benign criterion do not meet the Benign or Likely Benign thresholds, so the variant remains a 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.316C>G in MSH3 is a missense substitution predicted to produce NP_002430.3:p.(Gln106Glu). 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 pathogenic variant producing the same MSH3 amino-acid change, p.Gln106Glu, was identified in the reviewed evidence.	clinvar PMID:28944238
PS2	Not assessed	Not assessed: no documented parental genotypes or confirmed de novo occurrence is available for the proband's NM_002439.5:c.316C>G variant.
PS3	Not assessed	Not assessed: no validated variant-specific functional assay was reported, and the available record states that functional studies have not been performed.	clinvar
PS4	Not assessed	Not assessed: no exact-variant case-control counts, odds ratio, or statistically significant enrichment were reported for MSH3 c.316C>G.	PMID:28944238 PMID:29641532
PM1	Not met	Not met: MSH3 residue 106 is not supported by an approved critical-domain entry or statistically significant hotspot evidence.
PM2	Not met	Not met: gnomAD v4.1 total AF 0.000148697 exceeds the generic PM2 threshold of 0.0001.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	Not assessed	Not assessed: no affected-proband observation or confirmed pathogenic MSH3 variant in trans is documented for this autosomal-recessive condition.	PMID:25741868
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.316C>G in MSH3 is a missense substitution predicted to produce NP_002430.3:p.(Gln106Glu). 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: no validated pathogenic comparator substitution at MSH3 residue 106 was available for the required same-residue comparison.	pm5_candidates
PM6	Not assessed	Not assessed: no presumed de novo occurrence without parental testing is documented for NM_002439.5:c.316C>G.
PP1	Not assessed	Not assessed: no affected-relative co-segregation, unaffected-relative results, or informative meioses are reported for this variant.
PP2	Not met	Not met: the reviewed MSH3 cohort included recurrent missense variation, so a low rate of benign missense variation was not established.	PMID:28944238
PP3	Not met	Not met: REVEL 0.176 and SpliceAI max delta 0.001 are below PP3 supporting thresholds of >=0.644 and >=0.2, respectively.	revel spliceai generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no independently documented, highly specific MSH3-associated phenotype is available for the exact c.316C>G variant.	clinvar PMID:28944238 PMID:29641532
PP5	Not met	Not met: ClinVar variation 664483 has zero expert-panel submissions and no exact-variant expert-panel Pathogenic or Likely pathogenic classification.	clinvar
BA1	Not met	Not met: gnomAD v4.1 maximum reported AF 0.000196605 is 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 AF 0.000196605 is below the generic BS1 threshold of 0.01.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD v4.1 reports zero homozygotes, so the BS2 requirement for observed healthy homozygotes is not satisfied.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no validated variant-specific assay demonstrated normal MSH3 function, and the available record states that functional studies have not been performed.	clinvar
BS4	Not assessed	Not assessed: no tested unaffected relatives lacking the variant or other informative non-segregation evidence is documented.
BP1	Met	Met, supporting: available MSH3 evidence supports loss of function as the disease mechanism without establishing a pathogenic missense mechanism at residue 106.	PMID:25741868
BP2	Not assessed	Not assessed: no individual-level co-occurrence or phase result shows MSH3 c.316C>G in cis with a pathogenic variant.	PMID:25741868
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.316C>G in MSH3 is a missense substitution predicted to produce NP_002430.3:p.(Gln106Glu). 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: REVEL 0.176 meets the <=0.183 BP4 moderate threshold, with concordant SpliceAI max delta 0.001 <=0.1.	revel spliceai generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no verified patient-level alternative molecular diagnosis co-occurring with MSH3 c.316C>G is documented.	PMID:28944238 PMID:29641532 clinvar
BP6	Not met	Not met: the only ClinVar Likely benign assertion is single-submitter, while exact-variant expert-panel Benign or Likely benign submissions number zero.	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.316C>G in MSH3 is a missense substitution predicted to produce NP_002430.3:p.(Gln106Glu). 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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