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

PM2 supporting BP4 supporting

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

PM2 (Supporting): gnomAD v4.1 allele frequency 0.00015, extremely rare with no homozygotes observed.

BP4 (Supporting): REVEL 0.176, below the <0.250 benign computational threshold.

Overall: one supporting pathogenic and one supporting benign criterion (PM2, BP4) yield a Variant of Uncertain Significance under ACMG/AMP 2015.

Final determination: Under the generic ACMG/AMP 2015 fallback, one pathogenic supporting criterion plus one benign supporting criterion meets no classification threshold and is therefore 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	Not applicable: c.316C>G is a missense change (p.Gln106Glu), not a nonsense, frameshift, splice-site or other null variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no pathogenic variant producing the same amino-acid change at codon 106 has been reported.	PMID:28944238 clinvar
PS2	Not assessed	Not assessed: no proband-parent testing shows that this variant arose de novo.
PS3	Not assessed	Not assessed: no functional assay demonstrating a damaging effect on MSH3 was identified.
PS4	Not assessed	Not assessed: no case-control data report this exact variant in affected versus unaffected individuals.	PMID:28944238
PM1	Not assessed	Not assessed: no approved MSH3 critical-domain map is available to judge whether residue 106 lies in a functional domain.
PM2	Met	Met (supporting): gnomAD v4.1 allele frequency 0.00015, far below the rare-variant threshold, with no homozygotes observed.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no affected proband carries this variant in trans with a confirmed pathogenic MSH3 allele.	PMID:25741868
PM4	N/A	Not applicable: this missense change does not alter protein length, as PM4's in-frame indel or stop-loss premise requires.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no other pathogenic amino-acid substitution at residue 106 has been reported.	PMID:28944238
PM6	Not assessed	Not assessed: no case documents a presumed de novo occurrence of this variant.
PP1	Not assessed	Not assessed: no family segregation data link this variant to disease in affected relatives.
PP2	Not assessed	Not assessed: no MSH3-specific missense-enrichment rule establishes missense change as a rare disease mechanism.	PMID:28944238
PP3	Not met	Not met: REVEL 0.176 is below the PP3 threshold of >0.750.	revel final_classification_framework
PP4	Not assessed	Not assessed: no phenotype information is available for a patient carrying this exact variant.	PMID:28944238
PP5	Not met	Not met: ClinVar holds no expert-panel Pathogenic or Likely pathogenic submission for this exact variant.	clinvar
BA1	Not met	Not met: gnomAD v4.1 allele frequency 0.00015 is far below the 1% stand-alone benign threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 allele frequency 0.00015 is below the 0.3% threshold expected for a pathogenic MSH3 variant.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: no homozygotes are reported in gnomAD, so the variant is not observed in healthy homozygous adults.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no functional assay showing preserved MSH3 function has been reported for this variant.
BS4	Not assessed	Not assessed: no unaffected relatives lacking the variant were tested to demonstrate non-segregation.
BP1	Not assessed	Not assessed: it is not established that MSH3-related disease is caused predominantly by truncating variants.	PMID:28944238
BP2	Not assessed	Not assessed: no phase data place this variant in cis with a pathogenic or in trans with a benign variant.	PMID:25741868
BP3	N/A	Not applicable: this missense change does not alter protein length within a repeat region, as BP3 requires.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (supporting): REVEL 0.176 is below the BP4 threshold of <0.250, supporting a benign effect.	revel final_classification_framework
BP5	Not assessed	Not assessed: no carrier is reported to have a second, separate molecular diagnosis explaining their phenotype.
BP6	Not met	Not met: ClinVar has no expert-panel Benign or Likely benign submission for this exact variant.	clinvar
BP7	N/A	Not applicable: this missense change alters the protein sequence, so the silent-variant premise of BP7 does not hold.	generic_acmg_combination_rules

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