NM_002439.5:c.2800G>T

MSH3 · NP_002430.3:p.(Gly934Cys) · NM_002439.5

GRCh37: chr5:80109547 G>T · GRCh38: chr5:80813728 G>T

Gene: MSH3 Transcript: NM_002439.5

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

MSH3

Transcript

NM_002439.5

Protein

NP_002430.3:p.(Gly934Cys)

gnomAD AF

4.956629491945477e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_002439.5:c.2800G>T (p.Gly934Cys) in MSH3 is a missense variant with extremely low population frequency (gnomAD v2.1 global AF=0.008%; v4.1 global AF=0.005%), meeting PM2 at supporting strength.

In silico analysis with REVEL (score 0.746) and BayesDel (score 0.283) provides weak support for a deleterious effect, meeting PP3 at supporting strength.

No variant-specific functional data, case-control data, segregation data, or de novo observations are available. ClinVar classifies this variant as Uncertain significance (0-star).

Seven papers cited in ClinVar submissions were reviewed in full text or abstract; none mention NM_002439.5:c.2800G>T or provide variant-specific evidence.

With only two supporting-level pathogenic criteria (PM2_supporting, PP3_supporting) and no benign criteria met, this variant is classified as a Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 guidelines.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	This is a missense substitution (c.2800G>T, p.Gly934Cys), not a null variant (nonsense, frameshift, or canonical +/-1,2 splice site). The generic PVS1 framework per ClinGen SVI recommendations (PMC6185798) is not applicable to missense variants.	pvs1_generic_framework
PS1	Not met	No previously established pathogenic variant causing the same amino acid change (Gly934Cys) at this position has been identified in ClinVar or the literature.	clinvar pm5_candidates
PS2	Not met	No de novo observation data (with confirmed maternity and paternity) are available for this variant.
PS3	Not met	No variant-specific functional studies are available. OncoKB reports no functional evidence for this variant. No paper among the reviewed publications tested this variant or a systematically characterized range that includes position Gly934.	oncokb
PS4	Not met	No case-control studies or prevalence data demonstrating enrichment of this variant in affected individuals versus controls are available. ClinVar reports three clinical laboratory submissions but without aggregated case counts for statistical comparison.	clinvar
PS5	N/A	PS5 is not a standard ACMG/AMP 2015 criterion. The generic ACMG framework does not define this criterion.
PM1	Not met	Residue p.Gly934 is not located in a statistically significant mutational hotspot (cancerhotspots.org reports no significant hotspot). No well-characterized functional domain has been specifically implicated at this residue with pathogenic enrichment data.
PM2	Met	This variant is extremely rare in population databases. gnomAD v2.1 global allele frequency is 0.008% (20/251,458 alleles) and gnomAD v4.1 global AF is 0.005% (80/1,614,000 alleles), both well below the 0.1% PM2 threshold. All observed alleles are concentrated in the South Asian population (SAS AF=0.065-0.083%); grpmax FAF is 0.043-0.068%. No homozygotes are observed.	gnomad_v2 gnomad_v4
PM3	N/A	Recessive disorder / in trans criterion; skipped per instructions as trivially not applicable.
PM4	N/A	Protein length change criterion; this is a missense substitution variant.
PM5	N/A	Unable to identify same-residue comparator variants with different pathogenic amino acid changes. The pm5_candidates search found no eligible comparators at residue Gly934.	pm5_candidates
PM6	Not met	No de novo observation data are available for this variant. PM6 requires a confirmed de novo event with maternity and paternity testing.
PP1	Not met	No segregation data are available for this variant in affected families.
PP2	Not assessed	Missense constraint (z-score) data for MSH3 was not available in the evidence brief. PP2 requires demonstrating that the gene has a low rate of benign missense variation with missense variants as a common disease mechanism. Cannot assess without gene-level missense constraint metrics.
PP3	Met	REVEL score of 0.746 supports a deleterious effect. BayesDel (noAF) score of 0.283 is borderline above threshold. SpliceAI predicts no splice impact (max delta = 0.00). Multiple lines of in silico evidence provide weak support for a deleterious effect on the gene product.	revel bayesdel spliceai
PP4	Not met	No patient-specific phenotype or family history data are available. PP4 requires the variant to be observed in a patient with a phenotype and family history highly specific for the disease.
PP5	Not met	ClinVar reports this variant as 'Uncertain significance' with review status 'criteria provided, single submitter' (0-star). PP5 requires a reputable source to classify the variant as pathogenic, ideally at expert-panel level. The current ClinVar classification does not meet this threshold.	clinvar
BA1	Not met	Global allele frequency in gnomAD is well below the 1% BA1 threshold (v2.1: 0.008%; v4.1: 0.005%).	gnomad_v2 gnomad_v4
BS1	Not met	Global allele frequency in gnomAD is below the 0.3% BS1 threshold (v2.1: 0.008%; v4.1: 0.005%). Highest subpopulation frequency is South Asian at 0.083%, still below 0.3%.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygotes are observed in gnomAD v2.1 or v4.1 for this variant. BS2 requires observation in a healthy homozygous state.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies demonstrate no damaging effect for this variant. No functional data of any kind were identified.	oncokb
BS4	Not met	No non-segregation data are available for this variant.
BP1	N/A	BP1 applies to missense variants in genes where disease is primarily caused by truncating variants. While MSH3 loss-of-function is a supported disease mechanism, there is insufficient evidence that MSH3-associated disease is caused primarily by truncating variants to the exclusion of missense variants. Pathogenic missense variants in MMR genes are well-established.	pvs1_gene_context
BP2	Not met	No observation of this variant in trans with a known pathogenic variant in MSH3 is available.
BP4	Not met	REVEL score 0.746 and BayesDel score 0.283 support a deleterious rather than benign effect. SpliceAI predicts no splice impact but this alone is insufficient to meet BP4. Multiple lines of in silico evidence do not clearly suggest no impact on the gene product.	revel bayesdel spliceai
BP5	Not met	No observation of this variant in a case with an alternate molecular basis for disease is available.
BP6	Not met	ClinVar reports this variant as 'Uncertain significance,' not benign. BP6 requires a reputable source to classify the variant as benign.	clinvar
BP3	N/A	In-frame deletions/insertions criterion; this is a missense substitution variant.
BP7	N/A	This is a missense variant (c.2800G>T, p.Gly934Cys), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.