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.1 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.2 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).3 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.4 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.5
MSH3
Final classification
VUS
MSH3 c.2800G>T · p.Gly934Cys
MSH3
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.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, PP3 supporting; combination = 2 supporting, which maps to VUS.
Classification rationale
PM2PP3
VUS
MSH3 c.2800G>T
PM2 + PP3
→
VUS
2
revelbayesdelspliceai ↗
4
PMID:24493721 ↗PMID:24929052 ↗PMID:25394175 ↗PMID:25741868 ↗PMID:28492532 ↗PMID:33451724 ↗PMID:33516529 ↗
5
generic_acmg_combination_rules
Gene diagram
· NM_002439.5 · variants mapped to exon structure
MSH3
NM_002439.5
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 19 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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 v2.1: global AF=0.008% (20/251458)SAS AF=0.065%
✓
PP3
supporting
Pathogenic
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 score = 0.746 (deleterious range)BayesDel noAF score = 0.283 (borderline deleterious)SpliceAI max delta = 0.00 (no predicted splice effect)
Assessed · not applied
Pathogenic
PS1
No previously established pathogenic variant causing the same amino acid change (Gly934Cys) at this position has been identified in ClinVar or the literature.
PS2
No de novo observation data (with confirmed maternity and paternity) are available for this variant.
PS3
No variant-specific functional studies are available.
PS4
No case-control studies or prevalence data demonstrating enrichment of this variant in affected individuals versus controls are available.
PM1
Residue p.Gly934 is not located in a statistically significant mutational hotspot (cancerhotspots.org reports no significant hotspot).
PM6
No de novo observation data are available for this variant.
PP1
No segregation data are available for this variant in affected families.
PP2
Missense constraint (z-score) data for MSH3 was not available in the evidence brief.
PP4
No patient-specific phenotype or family history data are available.
PP5
ClinVar reports this variant as 'Uncertain significance' with review status 'criteria provided, single submitter' (0-star).
Benign
BA1
Global allele frequency in gnomAD is well below the 1% BA1 threshold (v2.1: 0.008%; v4.1: 0.005%).
BS1
Global allele frequency in gnomAD is below the 0.3% BS1 threshold (v2.1: 0.008%; v4.1: 0.005%).
BS2
No homozygotes are observed in gnomAD v2.1 or v4.1 for this variant.
BS3
No well-established functional studies demonstrate no damaging effect for this variant.
BS4
No non-segregation data are available for this variant.
BP2
No observation of this variant in trans with a known pathogenic variant in MSH3 is available.
BP4
REVEL score 0.746 and BayesDel score 0.283 support a deleterious rather than benign effect.
BP5
No observation of this variant in a case with an alternate molecular basis for disease is available.
BP6
ClinVar reports this variant as 'Uncertain significance,' not benign.
N/A · 7
PVS1 · PM3 · PM4 · PM5 · BP1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 4.95663e-05; MAF= 0.00496%, 80/1614000 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000834395; MAF= 0.08344%, 76/91084 alleles, homozygotes = 0); grpmax FAF= 0.00068343.
v2.1
This variant is present in gnomAD v2.1 (AF= 7.95361e-05; MAF= 0.00795%, 20/251458 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000653253; MAF= 0.06533%, 20/30616 alleles, homozygotes = 0); grpmax FAF= 0.00043223.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.005%
· 80 / 1,614,000
0 hom · FAF 0.068%
0 hom · FAF 0.068%
South Asian 76 / 91,084 |
0.083% |
Remaining individuals 3 / 62,484 |
0.0048% |
East Asian 1 / 44,890 |
0.0022% |
+ 7 not observed (Admixed American, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
0.008%
· 20 / 251,458
0 hom · FAF 0.043%
0 hom · FAF 0.043%
South Asian 20 / 30,616 |
0.065% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories). (ClinVarID = 852407)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.746. BayesDel score = 0.282801.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MSH3, a DNA mismatch repair protein, is frequently mutated in colorectal cancers.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 7 PMIDs not cited in assessment
24493721 ↗
American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.
CLINVAR
25394175 ↗
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR
33451724 ↗
Endometrial cancer: A society of gynecologic oncology evidence-based review and recommendations, part II.
CLINVAR
33516529 ↗
Endometrial cancer: A society of gynecologic oncology evidence-based review and recommendations.
CLINVAR