About MSH2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH2 c.366+1G>A, 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. 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
PVS1Very strong
PVS1 · very strong
NM_000251.2:c.366+1G>A is a canonical splice donor variant (IVS+1) in MSH2 exon 2. Exon 2 spans 155 nucleotides (c.212 to c.366), which is not divisible by 3; skipping or cryptic splice activation is predicted to disrupt the reading frame, introduce a premature termination codon, and trigger nonsense-mediated decay. Under InSiGHT MSH2 VCEP v2.0, IVS±1 variants where exon skipping disrupts the reading frame and is predicted to undergo NMD qualify for PVS1 at very_strong strength. The same genomic position with a G>C substitution (g.47408556G>C) was classified by the VCEP pilot as PVS1, confirming precedent.
PM2Supporting
PM2 · supporting
NM_000251.2:c.366+1G>A is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Under InSiGHT MSH2 VCEP v2.0, PM2_Supporting is met when the variant is absent or has an allele frequency <0.00002 (<1 in 50,000 alleles) in gnomAD v4. The VCEP pilot variants spreadsheet also applied PM2_supporting to the same-position variant g.47408556G>C.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MSH2 Version 2.0 v2.0 criteria-combination framework was evaluated deterministically with applied criteria: PVS1 very strong, PM2 supporting; no rule matched the adjudicated criteria.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from 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.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
8 reported laboratory submissions
6 Pathogenic · 2 Likely pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
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
3 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV51878772, n = 3 times).
Context only
COSMIC ↗
For specialists
Technical detail
ACMG/AMP criteria under ClinGen MSH2 VCEP v2.0, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 10 not met · 0 not assessed · 14 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000251.2:c.366+1G>A is a canonical +1 splice donor variant in MSH2 exon 2. Exon 2 skipping is predicted to disrupt the reading frame (155 bp, not divisible by 3) and trigger nonsense-mediated decay, qualifying for PVS1 at very_strong strength under InSiGHT MSH2 VCEP v2.0.
The variant is absent from all queried population databases (gnomAD v2.1, v4.1, and gnomAD-Canada v1.0), meeting PM2_Supporting under the VCEP threshold of <0.00002 allele frequency.
The same genomic position with a different nucleotide change (g.47408556G>C, equivalent to c.366+1G>C) was classified as Pathogenic by the InSiGHT VCEP pilot with PVS1 and PM2_Supporting, providing strong precedent for the pathogenicity of splice disruption at this position.
The variant has been reported in ClinVar as Pathogenic by 6 clinical laboratories and Likely Pathogenic by 2 laboratories (ClinVar ID 245947). It has been observed in COSMIC in 3 somatic cancer specimens (COSV51878772).
No literature evidence was found mentioning the exact variant (c.366+1G>A). Thirteen publications were triaged and reviewed; none contained variant-specific clinical, functional, segregation, or de novo data.
Applying InSiGHT MSH2 VCEP v2.0 classification rules: PVS1 (very_strong) + PM2_Supporting (supporting) meets Rule 4 (1 Very Strong + ≥2 Supporting = Pathogenic) or Rule 1 (1 Very Strong = Pathogenic). The overall classification is Pathogenic.
No criteria match.
Met · 2
PVS1 Very strongNM_000251.2:c.366+1G>A is a canonical splice donor variant (IVS+1) in MSH2 exon 2. Exon 2 spans 155 nucleotides (c.212 to c.366), which is not divisible by 3; skipping or cryptic splice activation is predicted to disrupt the reading frame, introduce a premature termination codon, and trigger nonsense-mediated decay. Under InSiGHT MSH2 VCEP v2.0, IVS±1 variants where exon skipping disrupts the reading frame and is predicted to undergo NMD qualify for PVS1 at very_strong strength. The same genomic position with a G>C substitution (g.47408556G>C) was classified by the VCEP pilot as PVS1, confirming precedent. Details ▾Hide ▴
Evidence considered
- Canonical +1 splice donor variant (IVS+1 of intron 2)
- Exon 2 is 155 bp
- skipping is out-of-frame and predicted to trigger NMD
- VCEP pilot: same position (c.366+1G>C
- g.47408556G>C) classified as Pathogenic with PVS1
- MSH2 loss-of-function is an established disease mechanism for Lynch syndrome (autosomal dominant)
Sources
cspec ↗vcep_vcep_pilot_variants_mmrvcep_pvs1_decisiontree_mmrpvs1_gene_contextpvs1_variant_assessment
PM2 SupportingNM_000251.2:c.366+1G>A is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Under InSiGHT MSH2 VCEP v2.0, PM2_Supporting is met when the variant is absent or has an allele frequency <0.00002 (<1 in 50,000 alleles) in gnomAD v4. The VCEP pilot variants spreadsheet also applied PM2_supporting to the same-position variant g.47408556G>C. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes)
- Absent from gnomAD v4.1 (exomes)
- Absent from gnomAD-Canada v1.0 (genomes)
Sources
Not met · 10 · evaluated, threshold not reached
PS2 No de novo observations were identified in the reviewed literature. No parental testing or de novo reports are available for NM_000251.2:c.366+1G>A. Details ▾Hide ▴
Still missing
- No de novo data available for this variant
PS3 No calibrated functional assay data or variant-specific functional studies were identified for NM_000251.2:c.366+1G>A in the reviewed literature. The InSiGHT MMR VCEP functional assay SVI documentation does not contain data for this specific variant. While the variant is at a canonical splice donor and is predicted null by mechanism, PS3 requires experimental functional evidence (calibrated assays with functional odds for pathogenicity), which is not available. Details ▾Hide ▴
Still missing
- No functional assay data for this exact variant
PP1 No co-segregation data is available for NM_000251.2:c.366+1G>A. None of the reviewed papers report pedigree-level segregation analysis for this specific variant. Details ▾Hide ▴
Still missing
- No co-segregation data available
PP4 No patient-specific tumor phenotype data (MSI status or IHC for MMR proteins) is available for carriers of NM_000251.2:c.366+1G>A in the case materials. The variant has been observed in COSMIC (3 somatic occurrences) but this does not constitute patient constitutional tumor phenotype evidence meeting PP4 thresholds under the VCEP. Details ▾Hide ▴
Evidence considered
- COSMIC: 3 somatic occurrences (COSV51878772) — not PP4-level evidence
Still missing
- No tumor MSI/IHC data for germline carriers
BA1 NM_000251.2:c.366+1G>A is absent from all queried gnomAD datasets. Under InSiGHT MSH2 VCEP v2.0, BA1 requires a gnomAD v4 Grpmax filtering allele frequency >=0.001 (0.1%). The variant does not meet this threshold. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- v4.1
- and Canada v1.0
Sources
BS1 NM_000251.2:c.366+1G>A is absent from gnomAD v4. Under InSiGHT MSH2 VCEP v2.0, BS1 requires a gnomAD v4 Grpmax filtering allele frequency >=0.0001 and <0.001. The variant is absent and does not meet this threshold. Details ▾Hide ▴
BS2 No evidence of co-occurrence in trans with a known pathogenic MSH2 variant was identified in the reviewed literature. No healthy adult carriers were identified to satisfy BS2. Details ▾Hide ▴
Still missing
- No co-occurrence data available
BS3 No functional studies demonstrating a benign effect were identified for NM_000251.2:c.366+1G>A. The InSiGHT MMR VCEP calibrated functional assays do not contain data for this variant. The VCEP BS3_Strong rule for intronic variants showing no mRNA aberration is also not met — no mRNA splicing assay data (with NMD inhibition) is available. Details ▾Hide ▴
Still missing
- No functional data showing proficient splicing or normal protein function
BS4 No segregation data demonstrating lack of co-segregation with disease was identified for NM_000251.2:c.366+1G>A. Details ▾Hide ▴
Still missing
- No co-segregation data available
BP5 No tumor phenotype data (MSS tumors, retained MMR protein expression, or BRAF V600E/MLH1 methylation) is available to suggest a benign interpretation for NM_000251.2:c.366+1G>A. Details ▾Hide ▴
Still missing
- No tumor data suggesting benign effect
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AInSiGHT MSH2 VCEP v2.0 PS1 applies to (a) predicted missense substitutions encoding the same amino acid change as a previously established P/LP variant, or (b) variants affecting the same non-canonical splice nucleotide as a confirmed P/LP splice variant. NM_000251.2:c.366+1G>A is a canonical (+1) splice variant, not a missense variant and not at a non-canonical splice nucleotide. PS1 is not applicable. Details ▾Hide ▴
Sources
PS4 VCEPInSiGHT MSH2 VCEP v2.0 states PS4 is not utilized due to availability of tumor IHC data (PP4) for variant classification. VCEP explicitly marks PS4 as Not Applicable. Details ▾Hide ▴
Sources
PM1 VCEPInSiGHT MSH2 VCEP v2.0 explicitly states PM1 is not applicable. The VCEP rationale: 'There are no recognized mutational hot spots that could be used for classification purposes. While there are functional domains in the MMR genes, the distribution of pathogenic variants is generalized over all the domains.' Details ▾Hide ▴
Evidence considered
- VCEP: PM1 not applicable for MMR genes
- no mutational hotspots with recognized classification utility
Sources
PM5 N/AInSiGHT MSH2 VCEP v2.0 PM5 applies to missense changes at an amino acid residue where a different missense change was classified as P/LP. NM_000251.2:c.366+1G>A is a canonical splice site variant, not a missense substitution, and does not map to an amino acid residue in a way that permits PM5 application. Details ▾Hide ▴
Evidence considered
- Variant is not missense
- PM5 candidate search returned no eligible candidates
Sources
cspec ↗pm5_candidates
PM6 VCEPInSiGHT MSH2 VCEP v2.0 explicitly marks PM6 as Not Applicable. Details ▾Hide ▴
Sources
PP2 VCEPInSiGHT MSH2 VCEP v2.0 explicitly marks PP2 as Not Applicable. The VCEP rationale: 'Missense variant in a gene with low rate of benign missense changes does not apply.' Details ▾Hide ▴
Sources
PP3 N/AInSiGHT MSH2 VCEP v2.0 PP3 for splice prediction applies only to non-canonical splicing nucleotides with SpliceAI delta score >=0.2. NM_000251.2:c.366+1G>A is at a canonical (+1) splice donor position. The VCEP PVS1 rule explicitly states: 'Not to be combined with PP3.' The splice effect is captured by PVS1. HCI prior is not applicable (variant not in missense HCI table). Details ▾Hide ▴
Evidence considered
- Canonical splice site variant
- PVS1 already applied
- PP3 not combined per VCEP instruction
Sources
PP5 VCEPInSiGHT MSH2 VCEP v2.0 explicitly marks PP5 as Not Applicable. 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.' Details ▾Hide ▴
Sources
BP1 VCEPInSiGHT MSH2 VCEP v2.0 explicitly marks BP1 as Not Applicable. 'Missense variant in a gene where only loss of function causes disease is not applicable.' Details ▾Hide ▴
Sources
BP2 VCEPInSiGHT MSH2 VCEP v2.0 explicitly marks BP2 as Not Applicable. The VCEP uses BS2 instead for co-occurrence evidence. Details ▾Hide ▴
Sources
BP4 N/ANM_000251.2:c.366+1G>A is a canonical (+1) splice donor variant. Although SpliceAI returns a max delta score of 0.00 (which is <=0.1), SpliceAI is not designed to accurately assess canonical ±1,2 splice site disruption. Applying BP4 would directly contradict the VCEP PVS1 assignment. The VCEP PVS1 rule captures the splice defect; BP4 is not applied when PVS1 is met for the same mechanism. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 — technical limitation at canonical sites
- PVS1 takes precedence
Sources
BP6 VCEPInSiGHT MSH2 VCEP v2.0 explicitly marks BP6 as Not Applicable. 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.' Details ▾Hide ▴
Sources
BP7 N/AInSiGHT MSH2 VCEP v2.0 BP7 applies to synonymous (silent) or intronic variants at or beyond -21/+7 that are predicted to have no splicing impact. Although c.366+1 is numerically within this range, it is the canonical +1 splice donor — the most critical nucleotide for 5' splice site recognition. BP7 is intended for deep intronic or exonic synonymous variants that are predicted benign, not for variants disrupting the consensus splice donor sequence. PVS1 captures the splicing impact of this variant. Details ▾Hide ▴
Evidence considered
- Canonical +1 splice donor
- not a benign intronic variant at a non-critical position
Sources
PS5 N/APS5 is not included in the InSiGHT MSH2 VCEP v2.0 criteria ruleset. The same-residue different amino acid change concept is covered by PM5 in this framework, and this variant is a splice variant, not a missense substitution. Details ▾Hide ▴
Sources
Identifiers
- Gene
- MSH2
- Transcript
- NM_000251.2
- Coding (HGVS c.)
- NM_000251.2:c.366+1G>A
- Protein (HGVS p.)
- NP_000242.1:p.?
- GRCh38
- chr2:47408556 G>A
- GRCh37
- chr2:47635695 G>A
- ClinVar
- 245947
- COSMIC
- COSV51878772
Gene diagram
Every interpreted variant in MSH2, mapped onto the exon structure of NM_000251.2. Select a row to find it on the plot.
MSH2NM_000251.2
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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- 0.660
How the predictions were used
PP3 N/AInSiGHT MSH2 VCEP v2.0 PP3 for splice prediction applies only to non-canonical splicing nucleotides with SpliceAI delta score >=0.2. NM_000251.2:c.366+1G>A is at a canonical (+1) splice donor position. The VCEP PVS1 rule explicitly states: 'Not to be combined with PP3.' The splice effect is captured by PVS1. HCI prior is not applicable (variant not in missense HCI table). Details ▾Hide ▴
Evidence considered
- Canonical splice site variant
- PVS1 already applied
- PP3 not combined per VCEP instruction
Sources
BP4 N/ANM_000251.2:c.366+1G>A is a canonical (+1) splice donor variant. Although SpliceAI returns a max delta score of 0.00 (which is <=0.1), SpliceAI is not designed to accurately assess canonical ±1,2 splice site disruption. Applying BP4 would directly contradict the VCEP PVS1 assignment. The VCEP PVS1 rule captures the splice defect; BP4 is not applied when PVS1 is met for the same mechanism. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 — technical limitation at canonical sites
- PVS1 takes precedence
Sources
BP7 N/AInSiGHT MSH2 VCEP v2.0 BP7 applies to synonymous (silent) or intronic variants at or beyond -21/+7 that are predicted to have no splicing impact. Although c.366+1 is numerically within this range, it is the canonical +1 splice donor — the most critical nucleotide for 5' splice site recognition. BP7 is intended for deep intronic or exonic synonymous variants that are predicted benign, not for variants disrupting the consensus splice donor sequence. PVS1 captures the splicing impact of this variant. Details ▾Hide ▴
Evidence considered
- Canonical +1 splice donor
- not a benign intronic variant at a non-critical position
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.66.
8 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
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PMID 16395668 ↗Systematic mRNA analysis for the effect of MLH1 and MSH2 missense and silent mutations on aberrant splicing.Auclair J et al. · 2006Systematic mRNA analysis of MLH1 and MSH2 missense and silent mutations for aberrant splicing. Examines whether nucleotide substitutions within coding sequences (missense/silent) or introns affect splicing. The abstract does not mention canonical splice site variants, and NM_000251.2:c.366+1G>A was not identified.Does not name this variant
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PMID 25194673 ↗Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations.Haraldsdottir S et al. · 2014Investigates whether colon and endometrial cancers with MMR deficiency can arise from somatic rather than germline mutations. Reports that some patients with MMR-deficient tumors lack germline MMR mutations, suggesting double somatic hits. NM_000251.2:c.366+1G>A was not identified in the full text.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.ACMG/AMP standards and guidelines for sequence variant interpretation. Provides the general framework for variant classification including PVS1, PS1-4, PM1-6, PP1-5, BA1, BS1-4, and BP1-7 criteria. NM_000251.2:c.366+1G>A was not identified in the full text.Does not name this variant
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PMID 29887214 ↗Using Somatic Mutations from Tumors to Classify Variants in Mismatch Repair Genes.Proposes using somatic mutations from tumors to classify constitutional variants in MMR genes. Argues that when somatic and constitutional mutations lead to the same molecular phenotype, somatic mutation data can aid variant classification. NM_000251.2:c.366+1G>A was not mentioned in the abstract.Does not name this variant
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PMID 11598466 ↗Practice parameters for the identification and testing of patients at risk for dominantly inherited colorectal cancer--supporting documentation.Church J et al. · 2001Practice parameters for identification and testing of patients at risk for dominantly inherited colorectal cancer. No abstract or full text was available for review. NM_000251.2:c.366+1G>A was not identified.Does not name this variant
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PMID 17939062 ↗Gene-related cancer spectrum in families with hereditary non-polyposis colorectal cancer (HNPCC).Geary J et al. · 2008Examines gene-related cancer spectrum in 130 families with HNPCC caused by mutations in MSH2 (n=64), MLH1 (n=62), or MSH6 (n=4). Reports cancer incidence compared to general population. NM_000251.2:c.366+1G>A was not mentioned in the abstract.Does not name this variant
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PMID 20301390 ↗Lynch Syndrome.Adam MP et al. · 1993GeneReviews entry on Lynch Syndrome. No abstract or full text was available for review. NM_000251.2:c.366+1G>A was not identified.Does not name this variant
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PMID 24310308 ↗ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis).ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, FAP, and MYH-associated polyposis). Discusses laboratory testing approaches. NM_000251.2:c.366+1G>A was not mentioned in the abstract.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
6 Pathogenic · 2 Likely pathogenic
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
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/245947/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-47635695-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47408556-G-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/2-47408556-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000251.2%3Ac.366%…
- OncoKB ↗www.oncokb.org/gene/MSH2/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=124532523
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Pathogenic (6 clinical laboratories) and as Likely pathogenic (2 clinical laboratories). (ClinVarID = 245947)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.66.
Somatic
This variant has previously been reported in somatic cancers (COSMIC; COSV51878772, n = 3 times).