About MSH3
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH3 c.2800G>T, p.(Gly934Cys)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
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.
PP3Supporting
PP3 · supporting
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.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
80 / 1,614,000 alleles
gnomAD v4.1: 80 / 1,614,000 alleles. Recorded AF 4.95663e-05. Recorded homozygote count 0.
gnomAD 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.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
3 reported laboratory submissions
3 Uncertain significance. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 18 not met · 1 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
No criteria match.
Met · 2
PM2 SupportingThis 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: global AF=0.008% (20/251
- 458)
- SAS AF=0.065%
- gnomAD v4.1: global AF=0.005% (80/1
- 614
- 000)
- SAS AF=0.083%
- grpmax FAF v2.1=0.043%
- v4.1=0.068%
- No homozygotes in any population
Sources
PP3 SupportingREVEL 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. Details ▾Hide ▴
Evidence considered
- REVEL score = 0.746 (deleterious range)
- BayesDel noAF score = 0.283 (borderline deleterious)
- SpliceAI max delta = 0.00 (no predicted splice effect)
Sources
Not met · 18 · evaluated, threshold not reached
PS1 No previously established pathogenic variant causing the same amino acid change (Gly934Cys) at this position has been identified in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- PM5 candidate search found no same-residue comparator variants.
Still missing
- No data on same amino acid change at this position.
Sources
clinvar ↗pm5_candidates
PS2 No de novo observation data (with confirmed maternity and paternity) are available for this variant. Details ▾Hide ▴
Still missing
- No de novo data available.
PS3 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. Details ▾Hide ▴
Evidence considered
- OncoKB reports unknown oncogenic effect with no variant-specific functional data.
Still missing
- No functional studies for this variant or a systematically characterized range that includes position Gly934.
Sources
PS4 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. Details ▾Hide ▴
Evidence considered
- ClinVar reports VUS from three clinical laboratories without case-count data suitable for PS4.
Still missing
- No case-control or prevalence enrichment data.
Sources
PM1 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. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org reports residue not in a statistically significant hotspot.
Still missing
- No domain-level pathogenic enrichment data for this residue.
PM6 No de novo observation data are available for this variant. PM6 requires a confirmed de novo event with maternity and paternity testing. Details ▾Hide ▴
Still missing
- No de novo data available.
PP1 No segregation data are available for this variant in affected families. Details ▾Hide ▴
Still missing
- No family segregation data available.
PP4 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. Details ▾Hide ▴
Still missing
- No clinical phenotype or family history data available for this assessment.
PP5 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. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance
- review status: criteria provided
- single submitter (0-star)
- not eligible for PP5.
Sources
BA1 Global allele frequency in gnomAD is well below the 1% BA1 threshold (v2.1: 0.008%; v4.1: 0.005%). Details ▾Hide ▴
Evidence considered
- gnomAD global AF = 0.005-0.008%
- far below 1% threshold.
Sources
BS1 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%. Details ▾Hide ▴
Evidence considered
- gnomAD global AF = 0.005-0.008%
- highest subpopulation AF (SAS) = 0.083%.
Sources
BS2 No homozygotes are observed in gnomAD v2.1 or v4.1 for this variant. BS2 requires observation in a healthy homozygous state. Details ▾Hide ▴
BS3 No well-established functional studies demonstrate no damaging effect for this variant. No functional data of any kind were identified. Details ▾Hide ▴
Evidence considered
- No functional studies available
- OncoKB reports unknown oncogenic effect.
Still missing
- No functional studies available.
Sources
BS4 No non-segregation data are available for this variant. Details ▾Hide ▴
Still missing
- No segregation data available.
BP2 No observation of this variant in trans with a known pathogenic variant in MSH3 is available. Details ▾Hide ▴
Still missing
- No trans configuration data available.
BP4 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. Details ▾Hide ▴
Evidence considered
- REVEL = 0.746 (inconsistent with benign prediction)
- BayesDel = 0.283 (borderline
- does not clearly support benign)
- SpliceAI = 0.00 (no splice effect)
Sources
BP5 No observation of this variant in a case with an alternate molecular basis for disease is available. Details ▾Hide ▴
Still missing
- No data on alternate molecular basis in variant carriers.
BP6 ClinVar reports this variant as 'Uncertain significance,' not benign. BP6 requires a reputable source to classify the variant as benign. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance
- not classified as benign.
Sources
Not assessed · 1 · no assessment recorded
PP2 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. Details ▾Hide ▴
Still missing
- MSH3 missense z-score / constraint metrics not available.
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis 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. Details ▾Hide ▴
Evidence considered
- Missense substitution
- variant does not fall into null-variant buckets eligible for PVS1.
Sources
PM3 N/ARecessive disorder / in trans criterion; skipped per instructions as trivially not applicable. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AProtein length change criterion; this is a missense substitution variant. Details ▾Hide ▴
No further detail was recorded.
PM5 N/AUnable to identify same-residue comparator variants with different pathogenic amino acid changes. The pm5_candidates search found no eligible comparators at residue Gly934. Details ▾Hide ▴
Evidence considered
- No same-residue pathogenic candidates found at p.Gly934 with a different amino acid change.
Sources
pm5_candidates
BP1 N/ABP1 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. Details ▾Hide ▴
Evidence considered
- MSH3 LoF mechanism supported but not demonstrably the sole/primary disease mechanism.
Sources
pvs1_gene_context
BP3 N/AIn-frame deletions/insertions criterion; this is a missense substitution variant. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AThis 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. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 is not a standard ACMG/AMP 2015 criterion. The generic ACMG framework does not define this criterion. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- MSH3
- Transcript
- NM_002439.5
- Coding (HGVS c.)
- NM_002439.5:c.2800G>T
- Protein (HGVS p.)
- NP_002430.3:p.(Gly934Cys)
- GRCh38
- chr5:80813728 G>T
- GRCh37
- chr5:80109547 G>T
- ClinVar
- 852407
Gene diagram
Every interpreted variant in MSH3, mapped onto the exon structure of NM_002439.5. Select a row to find it on the plot.
MSH3NM_002439.5
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in MSH3
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
80 / 1,614,000 alleles
AF 4.96e-05 · 0 homozygotes · FAF 0.000683
gnomAD v2.1
20 / 251,458 alleles
AF 7.95e-05 · 0 homozygotes · FAF 0.000432
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 5e-05 · 80 / 1,614,000 alleles · 0 hom · FAF 0.00068
| South Asian76 / 91,084 | 0.00083 |
| Remaining individuals3 / 62,484 | 4.8e-05 |
| East Asian1 / 44,890 | 2.2e-05 |
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish).
gnomAD v2.1
AF 8e-05 · 20 / 251,458 alleles · 0 hom · FAF 0.00043
| South Asian20 / 30,616 | 0.00065 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals.
Statements
gnomAD 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.
gnomAD 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.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.746
- BayesDel
- 0.283
How the predictions were used
PP3 SupportingREVEL 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. Details ▾Hide ▴
Evidence considered
- REVEL score = 0.746 (deleterious range)
- BayesDel noAF score = 0.283 (borderline deleterious)
- SpliceAI max delta = 0.00 (no predicted splice effect)
Sources
BP4 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. Details ▾Hide ▴
Evidence considered
- REVEL = 0.746 (inconsistent with benign prediction)
- BayesDel = 0.283 (borderline
- does not clearly support benign)
- SpliceAI = 0.00 (no splice effect)
Sources
BP7 N/AThis 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. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.746. BayesDel score = 0.282801.
7 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 24493721 ↗American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.Lu KH et al. · 2014ASCO expert statement providing guidance on collection and use of cancer family history for oncology providers. NM_002439.5:c.2800G>T was not mentioned or discussed.Does not name this variant
-
PMID 24929052 ↗Endometrial cancer: a review and current management strategies: part II.SGO Clinical Practice Endometrial Cancer Working Group et al. · 2014SGO clinical practice review of endometrial cancer management strategies, part II. Focused on surgical adjuvant therapy for endometrial cancer. NM_002439.5:c.2800G>T was not mentioned.Does not name this variant
-
PMID 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.Hampel H et al. · 2015ACMG practice guideline on referral indications for cancer predisposition assessment. General guideline document; NM_002439.5:c.2800G>T was not mentioned.Does not name this variant
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PMID 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.Richards S et al. · 2015ACMG/AMP joint consensus recommendation for the interpretation of sequence variants. Foundational guideline that defines the classification framework but does not discuss any specific variant. NM_002439.5:c.2800G>T was not mentioned.Does not name this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017Sherloc comprehensive refinement of ACMG-AMP variant classification criteria. Methodological framework paper; does not discuss any specific MSH3 variant. NM_002439.5:c.2800G>T was not mentioned.Does not name this variant
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PMID 33451724 ↗Endometrial cancer: A society of gynecologic oncology evidence-based review and recommendations, part II.Hamilton CA et al. · 2021SGO evidence-based review and recommendations for endometrial cancer, part II (recurrence, fertility preservation, survivorship). No mention of MSH3 or NM_002439.5:c.2800G>T. Note: the full-text file retrieved contained unrelated content (a Portuguese-language philosophy paper); assessment based on title/abstract context.Does not name this variant
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PMID 33516529 ↗Endometrial cancer: A society of gynecologic oncology evidence-based review and recommendations.Hamilton CA et al. · 2021SGO evidence-based review of endometrial cancer covering histopathology, risk factors, surgical approach, and adjuvant therapy. MSH3 is mentioned in the context of MMR gene families but NM_002439.5:c.2800G>T is not discussed.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
80 / 1,614,000 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
3 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/852407/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/5-80109547-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr5-80813728-G-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/5-80813728-G-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002439.5%3Ac.2800…
- OncoKB ↗www.oncokb.org/gene/MSH3/G934C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MSH3+c.2800G%3ET
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD 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.
gnomAD 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.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
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
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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.