Variant classification summary

NM_002439.5:c.1313C>T

MSH3 · NP_002430.3:p.(Ala438Val) · NM_002439.5

GRCh37: chr5:79974885 C>T · GRCh38: chr5:80679066 C>T

Gene: MSH3 Transcript: NM_002439.5

Final call

VUS

BP4 supporting

Variant details

Gene

MSH3

Transcript

NM_002439.5

Protein

NP_002430.3:p.(Ala438Val)

gnomAD AF

0.0003463457732804459 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: BP4 supporting is met because REVEL is 0.145, below the 0.29 benign-supporting threshold.

Final determination: Under generic ACMG/AMP 2015 fallback rules, one supporting benign criterion does not satisfy a benign combination rule, so the variant remains 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: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: no established pathogenic Ala438Val variant is documented, while ClinVar reports Likely benign from 5 laboratories and Uncertain significance from 3.	clinvar
PS2	Not assessed	Not assessed: parental testing confirming both maternity and paternity, plus absence of family history, is not documented.
PS3	Not assessed	Not assessed: no variant-specific validated functional assay or experimental result is reported for MSH3 p.(Ala438Val).	oncokb PMID:25741868 PMID:26467025 PMID:29641532
PS4	Not assessed	Not assessed: no exact-variant affected-versus-control counts, odds ratio, or confidence interval were reported, so the >5.0 and CI-not-including-1.0 requirements cannot be evaluated.	gnomad_v4 PMID:24493721 PMID:25394175 PMID:29641532 PMID:33516529 PMID:39541563
PM1	Not met	Not met: residue 438 is not in a documented critical domain or statistically significant hotspot, and Cancer Hotspots found no MSH3 A438 hotspot.	hotspots cosmic
PM2	Not met	Not met: gnomAD v4.1 all-comers AF is 0.000346346, exceeding the generic PM2 threshold of <=0.0001.	gnomad_v4 PMID:25741868
PM3	Not assessed	Not assessed: no documented affected proband with a pathogenic variant in trans and no parental or offspring testing to establish phase.	clinvar
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not met	Not met: the residue-438 search found zero comparator candidates, and no different pathogenic missense change at Ala438 is established.	pm5_candidates clinvar
PM6	Not assessed	Not assessed: no assumed-de-novo observation or parental testing result is documented for the variant.
PP1	Not assessed	Not assessed: no affected relatives or informative variant-phenotype segregation data are documented.
PP2	Not assessed	Not assessed: evidence lacks both a gene-wide low benign-missense-rate measure and proof that missense variants commonly cause MSH3 disease.	gnomad_v4 pvs1_gene_context
PP3	Not met	Not met: missense REVEL 0.145 is below the generic PP3 supporting threshold of 0.644.	revel
PP4	Not assessed	Not assessed: no patient phenotype or family-history findings were supplied to establish a highly specific single-etiology disease presentation.
PP5	Not met	Not met: ClinVar variation 791261 has 0 expert-panel submissions and no exact-variant Pathogenic or Likely pathogenic expert-panel classification.	clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.00416115, below the generic BA1 stand-alone threshold of 0.05.	gnomad_v4 PMID:25741868
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.00416115, below the generic BS1 default threshold of 0.01.	gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports 5 homozygotes in v4.1, but healthy-adult status and early full penetrance are not established.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific validated functional assay or experimental result is reported showing that MSH3 p.(Ala438Val) has no damaging effect.	oncokb PMID:25741868 PMID:26467025 PMID:29641532
BS4	Not assessed	Not assessed: no affected relatives tested negative for the variant, and no family segregation study is documented.
BP1	Not assessed	Not assessed: MSH3 loss-of-function disease evidence is present, but no evidence shows truncating variants are the primary disease-causing variant class.	pvs1_gene_context
BP2	Not assessed	Not assessed: no documented cis pathogenic variant or fully penetrant dominant trans observation is available for this variant.	clinvar
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met at supporting: missense REVEL 0.145 is below the generic BP4 supporting threshold of 0.29.	revel
BP5	Not assessed	Not assessed: no documented case links this variant to disease alongside an independently established alternate molecular basis.
BP6	Not met	Not met: ClinVar variation 791261 has 0 expert-panel submissions, so its individual-laboratory Likely benign assertions cannot trigger BP6.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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