About MSH2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH2 c.609del, p.(Gly204GlufsTer10)
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong
NM_000251.3:c.609del is a frameshift deletion introducing a premature termination codon at codon 214 (p.Gly204GlufsTer10), well before the VCEP-defined cutoff of codon 891 in MSH2. The variant resides in exon 3 of 16 and is predicted to undergo nonsense-mediated decay. Under the InSiGHT MMR VCEP PVS1 decision tree, frameshift variants introducing a PTC at or before codon 891 meet PVS1 at Very Strong strength.
PM2Supporting
PM2 · supporting
NM_000251.3:c.609del is absent from gnomAD v2.1 (0 alleles) and gnomAD v4.1 (0 alleles). This satisfies the InSiGHT MSH2 VCEP PM2_Supporting rule requiring an allele frequency <0.00002 (<1 in 50,000 alleles) in gnomAD v4.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
Richards et.al., 2015 - Combining rules v2.0.0 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.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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 ClinGen MSH2 VCEP v2.0.0, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 6 not met · 2 not assessed · 19 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000251.3:c.609del (p.Gly204GlufsTer10) is a frameshift deletion in exon 3 of MSH2 that introduces a premature termination codon at position 214, well before the InSiGHT VCEP-defined cutoff of codon 891 for PVS1 application at Very Strong strength.
The variant is absent from population databases including gnomAD v2.1 and v4.1 (0 alleles across all populations), meeting the VCEP PM2_Supporting threshold of <1 in 50,000 alleles.
SpliceAI predicts no splice-altering effect (max delta score = 0.01), consistent with a frameshift deletion that exerts its effect at the protein level through premature truncation rather than aberrant splicing.
OncoKB curates this variant as Likely Oncogenic with a Likely Loss-of-function biological effect, consistent with the predicted truncating mechanism.
No benign evidence criteria (BA1, BS1, BS2, BS3, BS4, BP5) are met; the variant is absent from population databases, no functional data support benign effect, and no alternate molecular basis or negative segregation data exist.
Applying the InSiGHT MSH2 VCEP v2.0.0 combining rules: PVS1_VeryStrong + PM2_Supporting yields 1 Very Strong + 1 Supporting. The VCEP rule set does not define a specific rule for this exact combination (Rule 4 requires ≥2 Supporting for Pathogenic; Rule 10 requires 1 Moderate for LP). Falling back to generic ACMG/AMP 2015 combination rules (PMID:25741868): 1 PVS1-level evidence (minimum Strong equivalent) + 1 Supporting → Likely Pathogenic. PP1 and PP4 remain unassessed; if either is met at Supporting level, the classification would upgrade to Pathogenic under VCEP Rule 4.
No criteria match.
Met · 2
PVS1 Very strongNM_000251.3:c.609del is a frameshift deletion introducing a premature termination codon at codon 214 (p.Gly204GlufsTer10), well before the VCEP-defined cutoff of codon 891 in MSH2. The variant resides in exon 3 of 16 and is predicted to undergo nonsense-mediated decay. Under the InSiGHT MMR VCEP PVS1 decision tree, frameshift variants introducing a PTC at or before codon 891 meet PVS1 at Very Strong strength. Details ▾Hide ▴
Evidence considered
- Frameshift deletion at codon 204 creating PTC at codon 214 (exon 3/16)
- PTC codon 214 ≤ 891 cutoff per InSiGHT MSH2 VCEP v2.0.0 PVS1 rule
- NMD predicted — variant occurs well upstream of the last exon-junction
- Gene-level loss-of-function mechanism established for MSH2 in Lynch syndrome (CSPEC-confirmed)
Sources
PM2 SupportingNM_000251.3:c.609del is absent from gnomAD v2.1 (0 alleles) and gnomAD v4.1 (0 alleles). This satisfies the InSiGHT MSH2 VCEP PM2_Supporting rule requiring an allele frequency <0.00002 (<1 in 50,000 alleles) in gnomAD v4. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes)
- Absent from gnomAD v4.1 (exomes + genomes)
- AF = 0
- meeting VCEP threshold of <0.00002
Sources
Not met · 6 · evaluated, threshold not reached
PS2 No de novo occurrence has been reported for NM_000251.3:c.609del in any available database or publication. Exploratory literature and database searches found no evidence of confirmed de novo status with maternity and paternity confirmation. Details ▾Hide ▴
Evidence considered
- No de novo reports found in ClinVar
- literature
- or locus-specific databases
Still missing
- De novo status is rarely captured for founder/recurrent variants in Lynch syndrome
BA1 BA1 under the InSiGHT MSH2 VCEP requires a gnomAD v4 Grpmax filtering allele frequency ≥0.001 (0.1%). NM_000251.3:c.609del is absent from gnomAD v4.1 (AF = 0), so BA1 is not met. Details ▾Hide ▴
BS1 BS1 under the InSiGHT MSH2 VCEP requires a gnomAD v4 Grpmax filtering allele frequency ≥0.0001 and <0.001 (0.01-0.1%). The variant is absent from gnomAD v4.1, so BS1 is not met. Details ▾Hide ▴
Evidence considered
- AF = 0 in gnomAD v4.1 — does not meet BS1 threshold of ≥0.0001
Sources
BS2 No evidence of this variant observed in trans with a known pathogenic MSH2 variant in a patient with colorectal cancer after age 45 without CMMRD features. BS2 requires confirmed phase and specific clinical context not available for this case. Details ▾Hide ▴
Still missing
- No co-occurrence data available for this variant
BS4 No evidence of lack of co-segregation with disease has been reported for NM_000251.3:c.609del. BS4 requires a combined Bayes Likelihood Ratio showing no segregation, which is not available. Given the variant's association with Lynch syndrome, BS4 is unlikely to be met. Details ▾Hide ▴
Still missing
- No negative segregation data published for this variant
BP5 No evidence that this variant has been observed in a case with an alternate molecular basis for disease (e.g., BRAF V600E, MLH1 methylation, or MSS tumors inconsistent with MSH2 involvement). BP5 requires tumor data not available for this case. Details ▾Hide ▴
Still missing
- No tumor data available to assess alternate molecular basis
Not assessed · 2 · no assessment recorded
PP1 Co-segregation data was not available for adjudication. The exploratory search identified a possible Finnish founder study (PMID 9230861) and InSiGHT database annotations suggesting segregation with Lynch syndrome, but no full-text or database segregation statistics were accessible to calculate a Bayes Likelihood Ratio under the VCEP PP1 rule. Details ▾Hide ▴
Evidence considered
- Exploratory search noted possible Finnish founder literature for this variant
Still missing
- Segregation data (pedigrees
- meioses) needed to compute Bayes Likelihood Ratio per VCEP PP1 thresholds
- InSiGHT locus-specific database may contain segregation annotations
PP4 No tumor phenotype data (MSI status, IHC for MMR proteins) was available for this case. Under the InSiGHT VCEP, PP4 requires MSI-H tumors and/or loss of MMR protein expression consistent with the variant location. Without tumor data, PP4 cannot be evaluated. Details ▾Hide ▴
Still missing
- Tumor MSI/IHC data from carriers of this variant needed to apply VCEP PP4 rule
Not applicable · 19· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to missense substitutions encoding the same amino acid change as a known pathogenic variant, or to variants affecting the same non-canonical splice nucleotide. c.609del is a frameshift deletion, not a missense substitution or splice variant. Details ▾Hide ▴
No further detail was recorded.
PS3 N/AThe VCEP functional assay documentation (Functional-assay-SVI-documentation-MMR.xlsx) is targeted to missense, splice site, and synonymous variants. c.609del is a frameshift truncating variant whose pathogenic mechanism (loss of function via premature termination and NMD) is already captured by PVS1. Calibrated functional assays in the MMR VCEP framework are not designed or validated for frameshift null variants. Details ▾Hide ▴
Evidence considered
- VCEP functional assay matrix covers missense/splice/synonymous variants only
- Frameshift PTC mechanism already addressed by PVS1 Very Strong
PS4 VCEPPS4 is marked as Not Applicable by the InSiGHT MSH2 VCEP v2.0.0 specification. Details ▾Hide ▴
Sources
PM1 VCEPThe InSiGHT MSH2 VCEP v2.0.0 explicitly excludes PM1: '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 ▴
Sources
PM3 N/APM3 applies to recessive disorders where the variant is observed in trans with a second pathogenic variant. MSH2 Lynch syndrome is autosomal dominant; PM3 is not applicable to this inheritance pattern. No biallelic CMMRD reports with this variant were identified. Details ▾Hide ▴
No further detail was recorded.
PM4 VCEPPM4 is marked as Not Applicable by the InSiGHT MSH2 VCEP v2.0.0 specification. Protein-length changes due to frameshift are captured by PVS1 in this framework. Details ▾Hide ▴
Sources
PM5 N/APM5 requires a missense change at an amino acid residue where a different missense change has been classified as pathogenic. c.609del is a frameshift deletion, not a missense variant. PM5 candidate search confirmed ineligibility. Details ▾Hide ▴
No further detail was recorded.
PM6 VCEPPM6 is marked as Not Applicable by the InSiGHT MSH2 VCEP v2.0.0 specification. Details ▾Hide ▴
Sources
PP2 VCEPPP2 is marked as Not Applicable by the InSiGHT MSH2 VCEP v2.0.0 specification. Details ▾Hide ▴
Sources
PP3 N/APP3 under the InSiGHT MSH2 VCEP requires either a missense variant with HCI prior >0.68 (for Supporting) or a non-canonical splice variant with SpliceAI delta ≥0.2. c.609del is a frameshift deletion, not a missense substitution. SpliceAI predicts no splice impact (max delta = 0.01). HCI prior lookup is not applicable to deletions. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.01 — no predicted splice alteration
- HCI prior not applicable to non-substitution variants
Sources
PP5 VCEPPP5 is marked as Not Applicable for this VCEP by the InSiGHT MSH2 specification. 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.' Details ▾Hide ▴
Sources
BS3 N/AThe VCEP functional assay documentation covers missense, splice site, and synonymous variants. BS3 requires calibrated functional assays showing no damaging effect. For a frameshift truncating variant like c.609del, the pathogenic mechanism (premature termination, NMD) is inherently damaging; calibrated functional assays in the MMR framework are not designed for null variants. The VCEP functional assay flowchart addresses residue-level function, not truncation-based loss of function. Details ▾Hide ▴
Evidence considered
- VCEP functional assay matrix designed for missense/splice/synonymous variants
- Frameshift truncation mechanism addressed by PVS1
BP1 VCEPBP1 is marked as Not Applicable by the InSiGHT MSH2 VCEP v2.0.0 specification. Details ▾Hide ▴
Sources
BP2 VCEPBP2 is marked as Not Applicable by the InSiGHT MSH2 VCEP. The VCEP uses BS2 instead for co-occurrence evidence. Details ▾Hide ▴
Sources
BP3 VCEPBP3 applies to in-frame deletions/insertions in repetitive regions without known function. c.609del is a frameshift (not in-frame) deletion, so BP3 is not applicable. Details ▾Hide ▴
Sources
BP4 N/ABP4 under the InSiGHT MSH2 VCEP requires either a missense variant with HCI prior <0.11 or an intronic/synonymous variant with SpliceAI delta ≤0.1. c.609del is a frameshift coding deletion — neither a missense nor an intronic/synonymous variant. HCI prior is not computed for deletions. Details ▾Hide ▴
Evidence considered
- Frameshift deletion not eligible for HCI prior or SpliceAI-based BP4
Sources
BP6 VCEPBP6 is marked as Not Applicable for this VCEP by the InSiGHT MSH2 specification. 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.' Details ▾Hide ▴
Sources
BP7 N/ABP7 applies to synonymous (silent) or intronic variants at or beyond -21/+7 (5'/3' exonic). c.609del is a coding frameshift deletion, not a synonymous or intronic variant. Details ▾Hide ▴
Sources
PS5 N/APS5 is not defined in the InSiGHT MSH2 VCEP v2.0.0 criteria specification. Details ▾Hide ▴
Sources
Identifiers
- Gene
- MSH2
- Transcript
- NM_000251.3
- Coding (HGVS c.)
- NM_000251.3:c.609del
- Protein (HGVS p.)
- NP_000242.1:p.(Gly204GlufsTer10)
- GRCh38
- chr2:47410335 GA>G
- GRCh37
- chr2:47637474 GA>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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/APP3 under the InSiGHT MSH2 VCEP requires either a missense variant with HCI prior >0.68 (for Supporting) or a non-canonical splice variant with SpliceAI delta ≥0.2. c.609del is a frameshift deletion, not a missense substitution. SpliceAI predicts no splice impact (max delta = 0.01). HCI prior lookup is not applicable to deletions. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.01 — no predicted splice alteration
- HCI prior not applicable to non-substitution variants
Sources
BP4 N/ABP4 under the InSiGHT MSH2 VCEP requires either a missense variant with HCI prior <0.11 or an intronic/synonymous variant with SpliceAI delta ≤0.1. c.609del is a frameshift coding deletion — neither a missense nor an intronic/synonymous variant. HCI prior is not computed for deletions. Details ▾Hide ▴
Evidence considered
- Frameshift deletion not eligible for HCI prior or SpliceAI-based BP4
Sources
BP7 N/ABP7 applies to synonymous (silent) or intronic variants at or beyond -21/+7 (5'/3' exonic). c.609del is a coding frameshift deletion, not a synonymous or intronic variant. Details ▾Hide ▴
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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 10946232 ↗Structure and function of mismatch repair proteins.No paper-specific finding is recorded.
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PMID 11257106 ↗Deficient DNA mismatch repair: a common etiologic factor for colon cancer.No paper-specific finding is recorded.
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PMID 15528792 ↗Mutations associated with HNPCC predisposition -- Update of ICG-HNPCC/INSiGHT mutation database.No paper-specific finding is recorded.
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PMID 23391514 ↗Structural, molecular and cellular functions of MSH2 and MSH6 during DNA mismatch repair, damage signaling and other noncanonical activities.No paper-specific finding is recorded.
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PMID 24362816 ↗Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.No paper-specific finding is recorded.
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PMID 7726159 ↗Seven new mutations in hMSH2, an HNPCC gene, identified by denaturing gradient-gel electrophoresis.No paper-specific finding is recorded.
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PMID 8566964 ↗CpG dinucleotides in the hMSH2 and hMLH1 genes are hotspots for HNPCC mutations.No paper-specific finding is recorded.
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PMID 8592341 ↗Detection of new mutations in six out of 10 Swiss HNPCC families by genomic sequencing of the hMSH2 and hMLH1 genes.No paper-specific finding is recorded.
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 0.010
Open source ↗
ClinVar
Captured ClinVar source record
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 ↗
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/?term=NM_000251.3%3Ac.609del
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-47637474-GA-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47410335-GA-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000251.3%3Ac.609d…
- OncoKB ↗www.oncokb.org/gene/MSH2/G204Efs*10
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MSH2+c.609del
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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.