NM_002439.5:c.8G>A

MSH3 · NP_002430.3:p.(Arg3His) · NM_002439.5

GRCh37: chr5:79950554 G>A · GRCh38: chr5:80654735 G>A

Gene: MSH3 Transcript: NM_002439.5

Final call

Likely Benign

PM2 moderate BP1 supporting benign BP4 supporting benign

Variant details

Gene

MSH3

Transcript

NM_002439.5

Protein

NP_002430.3:p.(Arg3His)

gnomAD AF

3.1251445379348796e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_002439.5:c.8G>A (p.Arg3His) in MSH3 is a missense variant in exon 1. This variant is extremely rare in population databases (gnomAD v4.1 AF=3.13×10⁻⁶, 5/1,599,926 alleles; gnomAD v2.1 AF=4.32×10⁻⁶, 1/231,498 alleles; 0 homozygotes observed).

The variant has been reported in ClinVar as Uncertain significance by two clinical laboratories (ClinVar ID: 969087). No expert panel classification is available. The ClinVar-associated references (PMID:25394175, a cancer referral practice guideline, and PMID:28492532, the Sherloc classification framework paper) do not provide variant-specific evidence for NM_002439.5:c.8G>A.

Computational predictors do not support a deleterious effect: REVEL score 0.31 (below pathogenic threshold), BayesDel score -0.0159 (not damaging), and SpliceAI max delta 0.00 (no splicing impact predicted).

No functional studies, segregation data, de novo reports, or case-control observations have been published for this variant. OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence.

Evidence weighting: one moderate pathogenic criterion (PM2 — extremely low population frequency) and two supporting benign criteria (BP1 — missense in a primarily loss-of-function disease gene; BP4 — multiple concordant benign computational predictions). The net evidence is insufficient to classify this variant as pathogenic or benign, consistent with a variant of uncertain significance.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

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
BP3	N/A	BP3 applies to in-frame insertions/deletions in repetitive regions; this is a missense substitution variant.
PM3	N/A	PM3 applies to recessive disorders; MSH3 is not established as a recessive disease gene requiring biallelic variant assessment per standard ACMG/AMP criteria.
PM4	N/A	PM4 applies to in-frame insertions/deletions or stop-loss variants; this is a missense substitution variant.
PVS1	N/A	This is a missense variant (c.8G>A, p.Arg3His) in exon 1 of MSH3. It does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). The generic PVS1 framework is not applicable to this variant class.	pvs1_generic_framework
PS1	Not assessed	No evidence of a different nucleotide change at the same position (c.8) leading to the same amino acid change (p.Arg3His) has been identified in ClinVar, COSMIC, or the reviewed literature.
PS2	Not met	No de novo occurrence has been reported for this variant in any publication or database. No parentage-confirmed de novo observation is available.
PS3	Not met	No well-established functional studies demonstrating a damaging effect have been identified for this variant. OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence. In silico predictors (REVEL 0.31, BayesDel -0.016) do not support a deleterious effect.	oncokb revel bayesdel
PS4	Not met	The variant has not been observed in multiple unrelated probands with the same phenotype in peer-reviewed literature. ClinVar submissions (2 clinical laboratories) classify this variant as Uncertain significance, and the single ClinVar-associated reference (PMID:25394175) is a practice guideline that does not mention MSH3 or this variant.	clinvar
PS5	Not met	No reputable source has classified this variant as pathogenic. The ClinVar classification is Uncertain significance from two single-submitter clinical laboratories, and no expert panel review is available.	clinvar
PM1	Not met	The variant (p.Arg3His) is located at the extreme N-terminus of MSH3 (position 3 of 1137 amino acids), far from the conserved MutS domain that mediates DNA mismatch recognition. This residue is not within a known functional domain or a statistically significant mutational hotspot. Cancer Hotspots analysis confirms no significant clustering at this position.
PM2	Met	This variant is extremely rare in large population databases: gnomAD v2.1 AF=4.32×10⁻⁶ (1/231,498 alleles), gnomAD v4.1 AF=3.13×10⁻⁶ (5/1,599,926 alleles), grpmax FAF=1.25×10⁻⁶, and absent from gnomAD-Canada. All observed allele frequencies are well below the 0.1% PM2 threshold. No homozygous individuals have been observed. One ClinVar submitter (Labcorp/Invitae) noted potential data quality concerns at this position in gnomAD but did not provide alternative frequency data.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue pathogenic comparator variants identified at amino acid position 3. Automated PM5 candidate harvesting returned no candidates. Unable to confirm classic same-residue PM5 semantics.
PM6	Not met	No de novo occurrence of this variant has been reported in any publication or ClinVar submission. No parentage-confirmed data available.
PP1	Not met	No co-segregation data are available for this variant. No family studies or segregation analyses have been reported in the reviewed literature.
PP2	Not met	PP2 requires a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease. MSH3-related disease (autosomal recessive adenomatous polyposis) is primarily caused by biallelic loss-of-function variants. Missense variants are not the established predominant disease mechanism, and the gene does not meet PP2 criteria.
PP3	Not met	Multiple in silico predictors do not support a deleterious effect. REVEL score 0.31 (below pathogenic threshold of 0.5). BayesDel score -0.0159 (not damaging). SpliceAI max delta 0.00 (no splicing impact predicted). HCI prior not available for this gene. The computational evidence does not reach the threshold for PP3.	revel bayesdel spliceai
PP4	Not met	No specific phenotypic or clinical data are available for individuals carrying this variant. The variant has been observed in clinical testing laboratories reporting VUS classification, but no detailed phenotype information is provided.
PP5	Not met	The variant is classified as Uncertain significance in ClinVar (2 clinical laboratories), not as pathogenic or likely pathogenic from a reputable source. The ClinVar-associated references (PMID:25394175, PMID:28492532) do not provide variant-specific evidence: PMID:25394175 is a cancer referral practice guideline that does not mention MSH3, and PMID:28492532 is a classification refinement methodology paper (Sherloc) that does not discuss this specific variant. No expert panel classification is available.	clinvar
BA1	Not met	The variant is extremely rare in population databases, not common. The highest observed allele frequency is 0.00043% (gnomAD v4.1 NFE), far below the 1% BA1 threshold. The variant does not meet the stand-alone benign criterion for common population variants.	gnomad_v2 gnomad_v4
BS1	Not met	The variant allele frequency is far below the 0.3% BS1 threshold. Highest subpopulation AF is 0.0073% (gnomAD v2.1 AMR_XY) and overall maximum AF is 0.00043% (gnomAD v4.1 NFE). The variant is too rare to apply BS1.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous individuals have been observed in gnomAD (v2.1 or v4.1). No observation in trans with a pathogenic variant has been reported. BS2 requires observation in a healthy adult homozygous state or in trans with a pathogenic variant for a fully penetrant disorder — this evidence is absent.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies demonstrating no deleterious effect are available for this variant. While in silico predictors are not damaging, BS3 requires direct experimental evidence showing normal function, which has not been reported.
BS4	Not met	No non-segregation data are available. No family studies have been reported that would demonstrate lack of co-segregation with disease.
BP1	Met	This is a missense variant (p.Arg3His) in MSH3, a gene for which the established disease mechanism is primarily biallelic loss-of-function via truncating variants. MSH3-related autosomal recessive adenomatous polyposis is caused by biallelic LoF variants. A missense variant in a gene where primarily truncating variants are known to cause disease meets BP1.	pvs1_gene_context
BP2	Not met	No observation of this variant in trans with a known pathogenic variant in MSH3 has been reported. No data support BP2 application.
BP4	Met	Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.31 (below pathogenic threshold of 0.5). BayesDel score is -0.0159 (not damaging). SpliceAI predicts no splicing impact (max delta 0.00). The concordant benign predictions from multiple algorithm types support BP4.	revel bayesdel spliceai
BP5	Not assessed	No clinical data are available to determine whether an alternative molecular basis for disease has been identified in any proband carrying this variant. Assessment of BP5 requires case-level clinical context not provided in the available evidence.
BP6	Not met	ClinVar classification for this variant is Uncertain significance, not Benign or Likely benign. Two clinical laboratories have submitted VUS classifications. BP6 requires a reputable source to classify the variant as benign/likely benign, which is not met.	clinvar
BP7	Not met	BP7 applies to synonymous variants predicted to have no impact on splicing. This variant (c.8G>A, p.Arg3His) is a missense variant, not synonymous. BP7 criteria are not satisfied.

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