About MSH2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH2 c.211+9C>A, p.?
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign classification under the recorded framework.
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: 2
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is present at extremely low frequency in gnomAD v4.1 (overall allele frequency = 5.04 × 10⁻⁶; 8/1,588,690 alleles; 0 homozygotes), which is below the InSiGHT MSH2 VCEP threshold of <0.00002 (<1 in 50,000 alleles). Highest subpopulation frequency is in East Asian (AF = 0.000182; 8/43,960).
Benign criteria applied · 2
BP4Supporting
BP4 · supporting
SpliceAI predicts no splicing impact for this intronic variant (max delta score = 0.00 ≤ 0.1), meeting the InSiGHT MSH2 VCEP BP4 rule for intronic and synonymous variants as per Walker et al. 2023.
BP7Supporting
BP7 · supporting
This variant is intronic at position c.211+9, which is beyond +7 from the 3' end of exon 1, meeting the InSiGHT MSH2 VCEP BP7 rule for intronic variants at or beyond the -21/+7 boundaries. This variant may satisfy both BP7 and BP4.
Recorded classification: Likely benign
Richards et.al., 2015 - Combining rules v2.0.0 criteria-combination framework: matched Rule19 (Benign.Supporting >=2) with applied criteria: PM2 supporting, BP4 supporting benign, BP7 supporting benign; maps to Likely Benign.
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
8 / 1,588,690 alleles
gnomAD v4.1: 8 / 1,588,690 alleles. Recorded AF 5.0356e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.87447e-05; MAF= 0.00187%, 4/213394 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000249626; MAF= 0.02496%, 4/16024 alleles, homozygotes = 0); grpmax FAF= 8.497e-05.
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
5 reported laboratory submissions
4 Likely benign · 1 Uncertain significance. ClinVar API review status: criteria provided, conflicting classifications.
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
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Context only
COSMIC ↗
For specialists
Technical detail
ACMG/AMP criteria under ClinGen MSH2 VCEP v2.0.0, with the data and sources behind each one.
27 criteria with recorded statuses: 3 met · 12 not met · 0 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
This variant is an intronic substitution at c.211+9 in MSH2, located beyond the +7 splice boundary, meeting BP7 (supporting benign).
SpliceAI predicts no splicing impact (max delta = 0.00), meeting BP4 (supporting benign) for intronic variants under the InSiGHT MSH2 VCEP (Walker et al. 2023).
This variant is present at extremely low frequency in gnomAD v4.1 (overall AF = 5.04 × 10⁻⁶, 8/1,588,690 alleles, 0 homozygotes), meeting PM2 at supporting strength under the InSiGHT MSH2 VCEP threshold of <0.00002.
The grpmax filtering allele frequency in gnomAD v4.1 is 8.99 × 10⁻⁵ (0.009%), which is below the BS1 threshold (≥ 0.0001) and the BA1 threshold (≥ 0.001); therefore BS1 and BA1 are not met.
PVS1 is not applicable — this is an intronic variant at +9, not a null variant or canonical splice site variant under the InSiGHT MSH2 VCEP PVS1 decision tree.
No tumor MSI/IHC, co-segregation, de novo, functional assay, or case-control data are available for this variant. No publications specifically report NM_000251.3:c.211+9C>A.
Under the InSiGHT MSH2 VCEP v2.0.0 combining rules, two supporting benign criteria (BP4, BP7) meet Rule 19 (≥ 2 Benign Supporting → Likely Benign). One pathogenic supporting criterion (PM2) is also present but does not trigger a VCEP-defined conflict with benign supporting evidence.
No criteria match.
Met · 3
PM2 SupportingThis variant is present at extremely low frequency in gnomAD v4.1 (overall allele frequency = 5.04 × 10⁻⁶; 8/1,588,690 alleles; 0 homozygotes), which is below the InSiGHT MSH2 VCEP threshold of <0.00002 (<1 in 50,000 alleles). Highest subpopulation frequency is in East Asian (AF = 0.000182; 8/43,960). Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF = 5.036e-06
- below VCEP PM2 threshold of <0.00002
Sources
BP4 SupportingSpliceAI predicts no splicing impact for this intronic variant (max delta score = 0.00 ≤ 0.1), meeting the InSiGHT MSH2 VCEP BP4 rule for intronic and synonymous variants as per Walker et al. 2023. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00
- at or below the VCEP BP4 threshold of ≤ 0.1
Sources
BP7 SupportingThis variant is intronic at position c.211+9, which is beyond +7 from the 3' end of exon 1, meeting the InSiGHT MSH2 VCEP BP7 rule for intronic variants at or beyond the -21/+7 boundaries. This variant may satisfy both BP7 and BP4. Details ▾Hide ▴
Not met · 12 · evaluated, threshold not reached
PS1 No known pathogenic variant at the same non-canonical splice nucleotide (c.211+9) in MSH2. SpliceAI delta score of 0.00 would not meet the 'similar or worse splicing prediction' requirement even if a comparator existed. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00
- No pathogenic variant identified at c.211+9 in VCEP pilot variants
Sources
PS2 No de novo reports available for NM_000251.3:c.211+9C>A. No publications describe a de novo occurrence of this variant with confirmed parentage. Details ▾Hide ▴
Still missing
- No de novo data available
PS3 No functional assay data available for this intronic variant. Under the InSiGHT MSH2 VCEP, PS3 for intronic variants requires calibrated functional assay data or laboratory mRNA aberration studies with NMD inhibition; none have been performed for this variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 — no predicted splice impact
- but computational prediction alone is insufficient for PS3
Still missing
- No laboratory functional assay data for this specific variant
Sources
PP1 No co-segregation data available for this variant. No family studies or pedigree analyses reporting segregation of NM_000251.3:c.211+9C>A with disease have been identified. Details ▾Hide ▴
Still missing
- No co-segregation data available
PP3 For intronic variants, the InSiGHT MSH2 VCEP PP3 requires a SpliceAI delta score ≥ 0.2 for non-canonical splice nucleotides (Supporting strength). SpliceAI predicts no splicing impact for this variant (max delta = 0.00). HCI prior is not applicable as this is not a missense substitution. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00
- below the VCEP PP3 threshold of ≥ 0.2
- HCI prior not applicable (intronic variant)
Sources
PP4 No tumor MSI or immunohistochemistry data available for this variant. PP4 under the InSiGHT MSH2 VCEP requires CRC/endometrial tumor MSI-H status and/or loss of MMR protein expression consistent with the variant gene; no such clinical data have been reported. Details ▾Hide ▴
BA1 gnomAD v4.1 grpmax filtering allele frequency is 8.99 × 10⁻⁵ (0.009%), which is below the InSiGHT MSH2 VCEP BA1 threshold of ≥ 0.001 (≥ 0.1%). Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF = 8.994e-05
- below BA1 threshold of ≥ 0.001
Sources
BS1 gnomAD v4.1 grpmax filtering allele frequency is 8.99 × 10⁻⁵ (0.009%), which is below the InSiGHT MSH2 VCEP BS1 threshold of ≥ 0.0001 (0.01%). Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF = 8.994e-05
- below BS1 threshold of ≥ 0.0001
Sources
BS2 No evidence of this variant occurring in trans with a known pathogenic MSH2 variant in a patient with colorectal cancer after age 45 and no CMMRD features. Details ▾Hide ▴
Still missing
- No co-occurrence in trans data available
BS3 No laboratory functional assay data available confirming absence of mRNA aberration or proficient MMR function for this specific intronic variant. The InSiGHT MSH2 VCEP BS3 for intronic variants requires laboratory assays conducted with NMD inhibition; SpliceAI computational predictions alone do not satisfy this criterion. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 suggests no splice impact
- but VCEP BS3 requires laboratory assay confirmation
- not computational prediction alone
Still missing
- No laboratory functional assay data for this specific variant
Sources
BS4 No lack-of-segregation data available. No pedigrees reporting absence of co-segregation of NM_000251.3:c.211+9C>A with disease. Details ▾Hide ▴
Still missing
- No segregation data available
BP5 No tumor data available to assess MSS status, MMR protein expression, BRAF V600E, or MLH1 methylation. BP5 under the InSiGHT MSH2 VCEP requires tumor phenotype data inconsistent with the gene demonstrating genetic variation. Details ▾Hide ▴
Still missing
- No tumor phenotype data available
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AIntronic variant at c.211+9 position; does not fall into any PVS1 bucket under the InSiGHT MSH2 VCEP v2.0.0 framework (not a null variant, not at IVS±1/2, and no mRNA assay demonstrating splicing aberration). Details ▾Hide ▴
Evidence considered
- Intronic variant at +9 in intron 1
- SpliceAI max delta = 0.00
Sources
PS4 VCEPCriterion not applicable for this VCEP per the InSiGHT MSH2 specification v2.0.0. Details ▾Hide ▴
Sources
PM1 VCEPCriterion not applicable for this VCEP per the InSiGHT MSH2 specification v2.0.0. Details ▾Hide ▴
Sources
PM5 N/AIntronic variant at c.211+9; PM5 requires a missense change at an amino acid residue with an established pathogenic missense comparator. This variant does not alter the amino acid sequence. Details ▾Hide ▴
PM6 VCEPCriterion not applicable for this VCEP per the InSiGHT MSH2 specification v2.0.0. Details ▾Hide ▴
Sources
PP2 VCEPCriterion not applicable for this VCEP per the InSiGHT MSH2 specification v2.0.0. Details ▾Hide ▴
Sources
PP5 VCEPCriterion not applicable for this VCEP per the InSiGHT MSH2 specification v2.0.0. Details ▾Hide ▴
Sources
BP1 VCEPCriterion not applicable for this VCEP per the InSiGHT MSH2 specification v2.0.0. Details ▾Hide ▴
Sources
BP2 VCEPCriterion not applicable for this VCEP per the InSiGHT MSH2 specification v2.0.0 (BS2 is used instead). Details ▾Hide ▴
Sources
BP3 VCEPSkipped — trivially not applicable (in-frame deletion/insertion criterion, variant is a substitution). Details ▾Hide ▴
No further detail was recorded.
BP6 VCEPCriterion not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee per the InSiGHT MSH2 specification v2.0.0. Details ▾Hide ▴
Sources
PS5 N/ASkipped — not in the assessment list for this case. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- MSH2
- Transcript
- NM_000251.3
- Coding (HGVS c.)
- NM_000251.3:c.211+9C>A
- Protein (HGVS p.)
- NP_000242.1:p.?
- GRCh38
- chr2:47403411 C>A
- GRCh37
- chr2:47630550 C>A
- ClinVar
- 237381
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
8 / 1,588,690 alleles
AF 5.04e-06 · 0 homozygotes · FAF 8.99e-05
gnomAD v2.1
4 / 213,394 alleles
AF 1.87e-05 · 0 homozygotes · FAF 8.5e-05
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 5e-06 · 8 / 1,588,690 alleles · 0 hom · FAF 9e-05
| East Asian8 / 43,960 | 0.00018 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish).
gnomAD v2.1
AF 1.9e-05 · 4 / 213,394 alleles · 0 hom · FAF 8.5e-05
| East Asian4 / 16,024 | 0.00025 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 5.0356e-06; MAF= 0.00050%, 8/1588690 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000181984; MAF= 0.01820%, 8/43960 alleles, homozygotes = 0); grpmax FAF= 8.994e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.87447e-05; MAF= 0.00187%, 4/213394 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000249626; MAF= 0.02496%, 4/16024 alleles, homozygotes = 0); grpmax FAF= 8.497e-05.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingSpliceAI predicts no splicing impact for this intronic variant (max delta score = 0.00 ≤ 0.1), meeting the InSiGHT MSH2 VCEP BP4 rule for intronic and synonymous variants as per Walker et al. 2023. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00
- at or below the VCEP BP4 threshold of ≤ 0.1
Sources
BP7 SupportingThis variant is intronic at position c.211+9, which is beyond +7 from the 3' end of exon 1, meeting the InSiGHT MSH2 VCEP BP7 rule for intronic variants at or beyond the -21/+7 boundaries. This variant may satisfy both BP7 and BP4. Details ▾Hide ▴
PP3 For intronic variants, the InSiGHT MSH2 VCEP PP3 requires a SpliceAI delta score ≥ 0.2 for non-canonical splice nucleotides (Supporting strength). SpliceAI predicts no splicing impact for this variant (max delta = 0.00). HCI prior is not applicable as this is not a missense substitution. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00
- below the VCEP PP3 threshold of ≥ 0.2
- HCI prior not applicable (intronic variant)
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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
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PMID 15662714 ↗Identification of Muir-Torre syndrome among patients with sebaceous tumors and keratoacanthomas: role of clinical features, microsatellite instability, and immunohistochemistry.Ponti G et al. · 2005Reports Muir-Torre syndrome identification in patients with sebaceous tumors and keratoacanthomas using clinical features, MSI, and IHC. Discusses MMR gene mutations generally but NM_000251.3:c.211+9C>A is not identified.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 consensus guidelines for sequence variant interpretation (Richards et al. 2015). Establishes the generic framework for variant classification but does not discuss any specific MSH2 variants including NM_000251.3:c.211+9C>A.Does not name this variant
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PMID 15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.Trepanier A et al. · 2004National Society of Genetic Counselors recommendations for cancer genetic risk assessment and counseling. General practice guideline that does not discuss specific MSH2 variants including NM_000251.3:c.211+9C>A.Does not name this variant
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PMID 23535968 ↗Informing family members of individuals with Lynch syndrome: a guideline for clinical geneticists.Guideline for clinical geneticists on informing family members of individuals with Lynch syndrome. Discusses family communication strategies but does not report any specific MSH2 variants including NM_000251.3:c.211+9C>A.Does not name this variant
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PMID 25356965 ↗ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.ACMG policy statement on secondary findings in clinical genome-scale sequencing. Does not discuss specific MSH2 variants including NM_000251.3:c.211+9C>A.Does not name this variant
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PMID 25452455 ↗Hereditary colorectal cancer syndromes: American Society of Clinical Oncology Clinical Practice Guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology Clinical Practice Guidelines.ASCO endorsement of ESMO guidelines for hereditary colorectal cancer syndromes. Discusses MSH2 generally in the context of Lynch syndrome management but NM_000251.3:c.211+9C>A is not identified.Does not name this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Sherloc refinement of ACMG-AMP variant classification criteria. Provides a general classification framework but does not discuss specific MSH2 variants including NM_000251.3:c.211+9C>A.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
8 / 1,588,690 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
4 Likely benign · 1 Uncertain significance
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/237381/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-47630550-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47403411-C-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/2-47403411-C-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000251.3%3Ac.211%…
- OncoKB ↗www.oncokb.org/gene/MSH2/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MSH2+c.211+9C%3EA
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= 5.0356e-06; MAF= 0.00050%, 8/1588690 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000181984; MAF= 0.01820%, 8/43960 alleles, homozygotes = 0); grpmax FAF= 8.994e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.87447e-05; MAF= 0.00187%, 4/213394 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000249626; MAF= 0.02496%, 4/16024 alleles, homozygotes = 0); grpmax FAF= 8.497e-05.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Uncertain significance (1 clinical laboratory). (ClinVarID = 237381)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).