About MSH2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH2 c.942+3A>G, p.?
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 ClinGen MSH2 VCEP v2.0.0. 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: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PVS1Strong
PVS1 · strong
Published RNA studies reported that this non-canonical donor-site variant causes skipping of MSH2 exon 5. Exon 5 corresponds to c.793_942 (150 nucleotides), predicting an in-frame deletion of 50 amino acids, p.Gly265_Gln314del. Under the MSH2 VCEP splice-specific PVS1 framework, confirmed aberrant splicing for a non-canonical splice variant supports PVS1 use; a conservative PVS1_Strong assignment is supported, with human review needed to confirm the extent of loss of full-length transcript and final splice consequence weighting.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
Official CSPEC/VCEP final-classification framework from final_classification_framework.json (cspec_ruleset criteria-combination framework; Richards et al. 2015 combining rules as represented in the MSH2/InSiGHT specification).
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
3 / 11,582 alleles
gnomAD v4.1: 3 / 11,582 alleles. Recorded AF 0.000259023. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
No listed criterion applied
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen MSH2 VCEP v2.0.0, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 7 not met · 9 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The MSH2 c.942+3A>G (p.?) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar with predominantly likely pathogenic submissions, although some submissions classify it as uncertain significance.
This variant is absent from gnomAD v2.1 but is present in gnomAD v4.1 at 3/11,582 alleles (total AF 0.00025902) with grpmax FAF 0.00004967, which is above the MSH2 VCEP PM2 threshold of less than 0.00002 and below the BS1 threshold of at least 0.0001.
Published RNA studies reported that this variant disrupts MSH2 donor splicing and generates an exon 5-skipped transcript, supporting a true splice defect despite its non-canonical +3 position.
SpliceAI predicts a low splice effect with a maximum delta score of 0.02, which is below the MSH2 VCEP PP3 threshold of at least 0.2 and within the BP4 threshold of 0.1 or less, but this in silico result is inconsistent with the published RNA evidence.
No criteria match.
Met · 1
PVS1 StrongPublished RNA studies reported that this non-canonical donor-site variant causes skipping of MSH2 exon 5. Exon 5 corresponds to c.793_942 (150 nucleotides), predicting an in-frame deletion of 50 amino acids, p.Gly265_Gln314del. Under the MSH2 VCEP splice-specific PVS1 framework, confirmed aberrant splicing for a non-canonical splice variant supports PVS1 use; a conservative PVS1_Strong assignment is supported, with human review needed to confirm the extent of loss of full-length transcript and final splice consequence weighting. Details ▾Hide ▴
Rule
MSH2 VCEP PVS1 splice rule for non-canonical splice variants with confirmed RNA aberration; conservative use at Strong strength.
Evidence considered
- MSH2 c.942+3A>G was reported to interfere with exon 5 donor splicing and produce an mRNA lacking exon 5.
- A second RNA-focused study supported that nucleotide substitutions in MSH2 can be the direct cause of splicing defects and used minigene/in vitro transcription approaches.
Still missing
- Variant-level confirmation of the proportion of full-length versus aberrant transcript was not fully quantified in the retrieved evidence.
- Final confirmation that the exon 5-skipped transcript meets the exact MSH2 VCEP PVS1 splice endpoint should be reviewed by a human curator.
Sources
Not met · 7 · evaluated, threshold not reached
PM2 This variant is present in gnomAD v4.1 with grpmax FAF 0.00004967, which is above the MSH2 VCEP PM2 threshold of less than 0.00002. Although it is absent from gnomAD v2.1, the available gnomAD v4.1 frequency data do not support PM2. Details ▾Hide ▴
Rule
MSH2 VCEP PM2_Supporting requires gnomAD v4 AF < 0.00002.
Evidence considered
- gnomAD v4.1 total AC 3/11582, total AF 0.00025902, grpmax FAF 0.00004967
- Absent from gnomAD v2.1
Sources
PP3 SpliceAI predicts a low splice effect for this variant, with a maximum delta score of 0.02. This value is below the MSH2 VCEP PP3 threshold of at least 0.2 for a predicted splice defect, so PP3 is not met. Details ▾Hide ▴
Rule
MSH2 VCEP PP3 for non-canonical splice variants requires SpliceAI delta score >= 0.2.
Evidence considered
- SpliceAI DS_AL 0.02, DS_DL 0.02, max delta score 0.02
Sources
BA1 The gnomAD v4.1 grpmax FAF for this variant is 0.00004967, which is below the MSH2 VCEP BA1 threshold of at least 0.001. The available population frequency does not support BA1. Details ▾Hide ▴
Rule
MSH2 VCEP BA1 requires gnomAD v4 grpmax FAF >= 0.001.
Evidence considered
- gnomAD v4.1 grpmax FAF 0.00004967
Sources
BS1 The gnomAD v4.1 grpmax FAF for this variant is 0.00004967, which is below the MSH2 VCEP BS1 threshold of at least 0.0001 and less than 0.001. The available population frequency does not support BS1. Details ▾Hide ▴
Rule
MSH2 VCEP BS1 requires gnomAD v4 grpmax FAF >= 0.0001 and < 0.001.
Evidence considered
- gnomAD v4.1 grpmax FAF 0.00004967
Sources
BS3 Available RNA studies reported an abnormal splicing effect for this variant, with exon 5 skipping, rather than no mRNA aberration. This evidence argues against BS3. Details ▾Hide ▴
Rule
BS3 requires benign calibrated functional evidence or no associated mRNA aberration for intronic/synonymous variants.
Evidence considered
- Published RNA data reported exon 5 skipping for this variant.
Still missing
- No variant-specific benign functional assay or RNA study showing no aberrant splicing with nonsense-mediated decay inhibition was identified.
Sources
BP4 SpliceAI predicts a low splice effect for this variant, with a maximum delta score of 0.02, which is below the BP4 threshold of 0.1 or less. However, published RNA studies reported exon 5 skipping, so the available evidence does not support using BP4 as a benign criterion for this variant. Details ▾Hide ▴
Rule
BP4 for intronic variants uses SpliceAI <= 0.1, but direct experimental RNA evidence outweighs isolated benign prediction.
Evidence considered
- SpliceAI max delta score 0.02
- Published RNA studies reported exon 5 skipping
Still missing
- If BP4 is reconsidered, the conflict between SpliceAI and direct RNA evidence should be resolved by human review.
Sources
BP7 This intronic variant is at position c.942+3, which is closer to the splice donor site than the MSH2 VCEP BP7 boundary of +7 or beyond. The variant position does not meet BP7. Details ▾Hide ▴
Rule
MSH2 VCEP BP7 requires an intronic variant at +7 or beyond, or -21 or beyond on the acceptor side.
Evidence considered
- Variant position is +3 relative to the exon-intron boundary.
Sources
Not assessed · 9 · no assessment recorded
PS3 RNA evidence supports a splice defect, but the retrieved evidence does not provide a calibrated MMR functional assay result or a variant-specific functional assay classification mapped through the MMR functional assay flowchart for PS3. Details ▾Hide ▴
Rule
PS3 requires calibrated functional assay evidence or qualifying flowchart-based functional evidence.
Evidence considered
- Variant-specific RNA splicing evidence was identified.
- No calibrated protein or cell-based functional assay result for PS3 was identified.
Still missing
- No calibrated OddsPath or MMR functional assay readout for this specific variant was identified in the retrieved evidence.
Sources
cspec ↗PMID:10978353 ↗PMID:16395668 ↗vcep_f_u_n_c_t_i_o_n_a_l___a_s_s_a_y___s_v_i___d_o_c_u_m_e_n_t_a_t_i_o_n___m_m_rvcep_f_u_n_c_t_i_o_n_a_l___a_s_s_a_y___f_l_o_w_c_h_a_r_t1097835316395668
PS2 Published literature notes recurrent de novo occurrence of this variant, but the retrieved evidence does not provide case-level MSH2 VCEP de novo point data with confirmed parentage and qualifying tumor evidence needed for PS2 scoring. Details ▾Hide ▴
Rule
PS2 requires point-based de novo evidence under the MSH2 VCEP framework.
Evidence considered
- The variant has been described as recurrent and frequently de novo in the literature.
Still missing
- No case-level de novo scoring data were identified.
- No maternity/paternity-confirmed proband data meeting the MSH2 VCEP PS2 framework were identified.
Sources
PS1 No evidence was identified in the retrieved materials showing that a different variant affecting this same non-canonical splice nucleotide has already been established by this VCEP as pathogenic or likely pathogenic with similar or worse splicing prediction. Details ▾Hide ▴
Rule
PS1 for MSH2 non-canonical splice variants requires same-nucleotide pathogenic or likely pathogenic splice precedent with similar or worse SpliceAI prediction.
Evidence considered
- No same-nucleotide VCEP precedent was identified in the reviewed materials.
Still missing
- No same-nucleotide pathogenic or likely pathogenic splice precedent was identified in the retrieved evidence.
Sources
PM3 No evidence was identified showing this variant in trans with another pathogenic MMR variant in a case scored under the MSH2 VCEP PM3 framework. Details ▾Hide ▴
Rule
PM3 requires point-based in trans observations under the MSH2 VCEP framework.
Evidence considered
- No qualifying PM3 data were identified in the retrieved evidence.
Still missing
- No phase-confirmed trans observations with qualifying clinical context were identified.
Sources
PP4 No case-level microsatellite instability, mismatch repair protein expression, or tumor phenotype data were identified for this individual, so PP4 cannot be scored from the retrieved evidence. Details ▾Hide ▴
Rule
PP4 requires qualifying MSI-H and/or IHC evidence consistent with variant location under the MSH2 VCEP framework.
Evidence considered
- No tumor phenotype data meeting the MSH2 VCEP PP4 framework were identified.
Still missing
- No qualifying MSI, tumor genome, or immunohistochemistry data were identified.
Sources
cspec ↗vcep_t_a_b_l_e___f_o_r___c_m_m_r_d___d_i_a_g_n_o_s_i_s
PP1 No segregation dataset with a calculable Bayes likelihood ratio was identified, so PP1 cannot be assessed from the retrieved evidence. Details ▾Hide ▴
Rule
PP1 requires Bayes likelihood ratio-based co-segregation evidence.
Evidence considered
- No qualifying segregation evidence was identified.
Still missing
- No pedigree-based segregation analysis or Bayes likelihood ratio was identified.
Sources
BS2 No evidence was identified showing this variant in trans with a known pathogenic MSH2 variant in a qualifying individual without clinical manifestations of CMMRD, so BS2 cannot be assessed. Details ▾Hide ▴
Rule
BS2 requires a qualifying in trans observation in a case meeting the MSH2 VCEP conditions.
Evidence considered
- No qualifying BS2 evidence was identified.
Still missing
- No phase-confirmed trans observation with qualifying phenotype information was identified.
Sources
cspec ↗vcep_t_a_b_l_e___f_o_r___c_m_m_r_d___d_i_a_g_n_o_s_i_s
BS4 No lack-of-segregation dataset with a Bayes likelihood ratio was identified, so BS4 cannot be assessed from the retrieved evidence. Details ▾Hide ▴
Rule
BS4 requires Bayes likelihood ratio-based lack-of-segregation evidence.
Evidence considered
- No qualifying BS4 evidence was identified.
Still missing
- No pedigree-based lack-of-segregation analysis was identified.
Sources
BP5 No tumor series showing mismatch between tumor findings and the gene harboring this variant were identified, so BP5 cannot be assessed. Details ▾Hide ▴
Rule
BP5 requires qualifying tumor evidence under the MSH2 VCEP framework.
Evidence considered
- No qualifying BP5 evidence was identified.
Still missing
- No qualifying tumor-based evidence for BP5 was identified.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PS4 N/APS4 is not applicable for this MSH2 VCEP specification. Details ▾Hide ▴
Rule
MSH2 CSPEC: PS4 not applicable.
Evidence considered
- The MSH2 CSPEC marks PS4 as not applicable.
Sources
PM5 N/APM5 is a missense-specific criterion and does not apply to this intronic splice-region variant. Details ▾Hide ▴
Rule
PM5 applies to missense substitutions.
Evidence considered
- Variant type is intronic splice-region, not missense.
Sources
PM6 N/APM6 is not applicable for this MSH2 VCEP specification. Details ▾Hide ▴
Rule
MSH2 CSPEC: PM6 not applicable.
Evidence considered
- The MSH2 CSPEC marks PM6 as not applicable.
Sources
PM1 N/APM1 is not applicable for this MSH2 VCEP specification. Details ▾Hide ▴
Rule
MSH2 CSPEC: PM1 not applicable.
Evidence considered
- The MSH2 CSPEC marks PM1 as not applicable.
Sources
cspec ↗vcep_m_m_r___f_u_n_c_t_i_o_n_a_l___d_o_m_a_i_n_s
PP2 N/APP2 is not applicable for this MSH2 VCEP specification. Details ▾Hide ▴
Rule
MSH2 CSPEC: PP2 not applicable.
Evidence considered
- The MSH2 CSPEC marks PP2 as not applicable.
Sources
PP5 N/APP5 is not applicable for this MSH2 VCEP specification. Details ▾Hide ▴
Rule
MSH2 CSPEC: PP5 not applicable.
Evidence considered
- The MSH2 CSPEC marks PP5 as not applicable.
Sources
BP6 N/ABP6 is not applicable for this MSH2 VCEP specification. Details ▾Hide ▴
Rule
MSH2 CSPEC: BP6 not applicable.
Evidence considered
- The MSH2 CSPEC marks BP6 as not applicable.
Sources
BP3 N/ABP3 is not applicable for this MSH2 VCEP specification. Details ▾Hide ▴
Rule
MSH2 CSPEC: BP3 not applicable.
Evidence considered
- The MSH2 CSPEC marks BP3 as not applicable.
Sources
BP2 N/ABP2 is not applicable for this MSH2 VCEP specification. Details ▾Hide ▴
Rule
MSH2 CSPEC: BP2 not applicable.
Evidence considered
- The MSH2 CSPEC marks BP2 as not applicable.
Sources
BP1 N/ABP1 is not applicable for this MSH2 VCEP specification. Details ▾Hide ▴
Rule
MSH2 CSPEC: BP1 not applicable.
Evidence considered
- The MSH2 CSPEC marks BP1 as not applicable.
Sources
PM4 N/APM4 is not applicable for this MSH2 VCEP specification. Details ▾Hide ▴
Rule
MSH2 CSPEC: PM4 not applicable.
Evidence considered
- The MSH2 CSPEC marks PM4 as not applicable.
Sources
Identifiers
- Gene
- MSH2
- Transcript
- NM_000251.3
- Coding (HGVS c.)
- NM_000251.3:c.942+3A>G
- Protein (HGVS p.)
- NP_000242.1:p.?
- GRCh38
- chr2:47414421 A>G
- GRCh37
- chr2:47641560 A>G
Gene diagram
Every interpreted variant in MSH2, mapped onto the exon structure of NM_000251.3. Select a row to find it on the plot.
MSH2NM_000251.3
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 MSH2
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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
3 / 11,582 alleles
AF 0.000259 · 0 homozygotes · FAF 4.97e-05
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.00026 · 3 / 11,582 alleles · 0 hom · FAF 5e-05
| Remaining individuals1 / 444 | 0.0023 |
| European (non-Finnish)2 / 7,044 | 0.00028 |
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000259023; MAF= 0.02590%, 3/11582 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.00225225; MAF= 0.22523%, 1/444 alleles, homozygotes = 0); grpmax FAF= 4.967e-05.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SpliceAI predicts a low splice effect for this variant, with a maximum delta score of 0.02. This value is below the MSH2 VCEP PP3 threshold of at least 0.2 for a predicted splice defect, so PP3 is not met. Details ▾Hide ▴
Rule
MSH2 VCEP PP3 for non-canonical splice variants requires SpliceAI delta score >= 0.2.
Evidence considered
- SpliceAI DS_AL 0.02, DS_DL 0.02, max delta score 0.02
Sources
BP4 SpliceAI predicts a low splice effect for this variant, with a maximum delta score of 0.02, which is below the BP4 threshold of 0.1 or less. However, published RNA studies reported exon 5 skipping, so the available evidence does not support using BP4 as a benign criterion for this variant. Details ▾Hide ▴
Rule
BP4 for intronic variants uses SpliceAI <= 0.1, but direct experimental RNA evidence outweighs isolated benign prediction.
Evidence considered
- SpliceAI max delta score 0.02
- Published RNA studies reported exon 5 skipping
Still missing
- If BP4 is reconsidered, the conflict between SpliceAI and direct RNA evidence should be resolved by human review.
Sources
BP7 This intronic variant is at position c.942+3, which is closer to the splice donor site than the MSH2 VCEP BP7 boundary of +7 or beyond. The variant position does not meet BP7. Details ▾Hide ▴
Rule
MSH2 VCEP BP7 requires an intronic variant at +7 or beyond, or -21 or beyond on the acceptor side.
Evidence considered
- Variant position is +3 relative to the exon-intron boundary.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
3 / 11,582 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1577628936
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/418625/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-47641560-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47414421-A-G?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000251.3%3Ac.942%…
- OncoKB ↗www.oncokb.org/gene/MSH2
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= 0.000259023; MAF= 0.02590%, 3/11582 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.00225225; MAF= 0.22523%, 1/444 alleles, homozygotes = 0); grpmax FAF= 4.967e-05.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (5 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as likely pathogenic (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).