About MSH2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH2 c.2458+8C>G, 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: 0
Benign evidence criteria: 2
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 2
BP4Supporting
BP4 · supporting
The VCEP BP4 rule for intronic variants states: SpliceAI predicts no splicing impact with delta score ≤ 0.1. The SpliceAI max delta score for this variant is 0.04, satisfying this criterion at the Supporting strength level.
BP7Supporting
BP7 · supporting
The VCEP BP7 rule states that synonymous or intronic variants at or beyond −21/+7 (5′/3′ exonic) meet BP7 at Supporting strength. This variant is at position c.2458+8, which is beyond the +7 threshold.
Recorded classification: Likely benign
Richards et.al., 2015 - Combining rules v2.0.0 criteria-combination framework: matched Rule19 (Benign.Supporting >=2) with applied criteria: 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
33 / 1,613,836 alleles
gnomAD v4.1: 33 / 1,613,836 alleles. Recorded AF 2.04482e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.01783e-05; MAF= 0.00602%, 17/282494 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000254223; MAF= 0.02542%, 9/35402 alleles, homozygotes = 0); grpmax FAF= 0.00013492.
No listed criterion applied
SpliceAI score
0.040 maximum delta
Recorded SpliceAI maximum delta score: 0.040. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
13 reported laboratory submissions
10 Likely benign · 1 benign · 1 Likely Benign · 1 Benign.
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
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV105858622, n = 1 times).
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.
26 criteria with recorded statuses: 2 met · 14 not met · 0 not assessed · 10 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.2458+8C>G is an intronic variant in MSH2 located at position +8 of intron 14. SpliceAI predicts no splicing impact (max delta score 0.04), satisfying BP4 at Supporting benign strength per the InSiGHT MSH2 VCEP v2.0.0.
This variant is present in gnomAD v4.1 at a low frequency (33/1,613,836 alleles; AF=2.04e-05; grpmax FAF=8.99e-05) but does not meet the VCEP PM2 threshold (<0.00002) nor BS1 (≥0.0001), falling in an intermediate frequency range that neither supports nor refutes pathogenicity under VCEP rules.
As an intronic variant at position +8 (beyond the +7 boundary), BP7 applies at Supporting benign strength per VCEP rules. The variant may satisfy both BP7 and BP4.
This variant has been reported in ClinVar (ClinVar ID 135857) as Likely benign by 10 clinical laboratories and as Benign by 1 clinical laboratory, with no expert panel review to date. No published studies have specifically evaluated this variant for functional effects, segregation, or tumor phenotype.
No evidence is available for PVS1 (not a null variant), PS2 (no de novo reports), PS3 (no functional studies), PP1 (no segregation data), PP4 (no tumor MSI/IHC data), BS2 (no trans co-occurrence), BS3 (no laboratory functional assay), BS4 (no lack-of-segregation data), or BP5 (no tumor phenotype data).
Applying the InSiGHT MSH2 VCEP v2.0.0 combining rules: two Supporting benign criteria (BP4 + BP7) are met, satisfying Rule 19 (≥2 Benign Supporting → Likely Benign).
No criteria match.
Met · 2
BP4 SupportingThe VCEP BP4 rule for intronic variants states: SpliceAI predicts no splicing impact with delta score ≤ 0.1. The SpliceAI max delta score for this variant is 0.04, satisfying this criterion at the Supporting strength level. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.04 ≤ 0.1 — no predicted splicing impact
Sources
BP7 SupportingThe VCEP BP7 rule states that synonymous or intronic variants at or beyond −21/+7 (5′/3′ exonic) meet BP7 at Supporting strength. This variant is at position c.2458+8, which is beyond the +7 threshold. Details ▾Hide ▴
Not met · 14 · evaluated, threshold not reached
PVS1 This is an intronic variant at position c.2458+8, outside the canonical splice donor/acceptor consensus (±1,2). The VCEP PVS1 rules apply to nonsense/frameshift variants introducing PTC ≤ codon 891, large genomic alterations, IVS±1 or ±2 variants, or variants with mRNA-confirmed splicing aberration causing premature stop or in-frame deletion of a critical domain. SpliceAI predicts no splicing impact (max delta 0.04). No mRNA assay or minigene study has been performed for this variant. PVS1 is not applicable. Details ▾Hide ▴
Evidence considered
- Intronic +8 variant
- not in canonical splice consensus
- SpliceAI max delta 0.04 — no predicted splicing impact
- No RNA/mRNA assay data available
Still missing
- No RNA splicing assay data
Sources
PS1 This intronic variant does not encode an amino acid change, so the missense-based PS1 path is inapplicable. The non-canonical splice nucleotide PS1 path requires another variant at the same +8 position classified as Pathogenic or Likely Pathogenic with similar or worse SpliceAI prediction; no such comparator variant is known at the +8 position of MSH2 intron 14. Details ▾Hide ▴
Evidence considered
- Intronic variant
- no amino acid change
- No known pathogenic/LP comparator at +8 position
PS2 No de novo observations have been reported for this variant. The ClinVar submissions and published literature contain no mention of confirmed maternity and paternity testing demonstrating de novo occurrence. Details ▾Hide ▴
Evidence considered
- No de novo reports in ClinVar or literature
Still missing
- No de novo testing data
Sources
PS3 No calibrated functional assays have been performed on this variant. The variant is not listed in the VCEP Functional Assay SVI documentation for MMR genes, and no published functional study (in vitro MMR activity, protein expression, or splicing assay) has evaluated this specific variant. Details ▾Hide ▴
Evidence considered
- Variant absent from VCEP functional assay documentation
- No published functional studies found
Still missing
- No functional assay data available
Sources
vcep_functional_assay_svi_documentation_mmr
PM2 The VCEP PM2 rule requires absent/extremely rare allele frequency <0.00002 (<1 in 50,000 alleles) in gnomAD v4. This variant is present in gnomAD v4.1 with 33 alleles out of 1,613,836 (AF=2.04e-05, ~1 in 48,904 alleles), and the grpmax filtering allele frequency is 8.99e-05. Both values exceed the VCEP PM2 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 33/1
- 613
- 836 alleles
- AF=2.04e-05
- grpmax FAF=8.99e-05
- Allele count exceeds VCEP threshold of <1:50
- 000
Sources
PP1 No co-segregation data are available for this variant. No published pedigrees or segregation analyses report this variant segregating with Lynch syndrome or other MMR-deficient phenotypes in families. Details ▾Hide ▴
Evidence considered
- No published co-segregation data
- No pedigree analyses found
Still missing
- No segregation data available
Sources
PP3 The VCEP PP3 rules for non-canonical splice variants require a SpliceAI delta score ≥ 0.2 for supporting-level evidence. SpliceAI max delta score for this variant is 0.04, well below the threshold. The HCI prior missense path is inapplicable as this is an intronic variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.04 — below PP3 threshold of 0.2
- HCI prior not applicable (intronic variant)
Sources
PP4 No tumor MSI/IHC data are reported for patients carrying this variant. The VCEP PP4 rules require MSI-H tumors and/or loss of MMR protein expression consistent with the variant location; no such clinical data have been published or submitted to ClinVar for this variant. Details ▾Hide ▴
Evidence considered
- No MSI/IHC tumor data reported
Still missing
- No tumor phenotype data available
Sources
BA1 The VCEP BA1 rule requires gnomAD v4 grpmax filtering allele frequency ≥ 0.001 (0.1%). The grpmax FAF for this variant is 8.99e-05 (0.009%), which is an order of magnitude below the BA1 threshold. Details ▾Hide ▴
BS1 The VCEP BS1 rule requires gnomAD v4 grpmax filtering allele frequency ≥ 0.0001 (0.01%) and < 0.001 (0.1%). The grpmax FAF for this variant is 8.99e-05 (0.009%), which falls just below the 0.0001 lower threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4 grpmax FAF=8.99e-05
- slightly below BS1 lower threshold of 0.0001
Sources
BS2 No observation of this variant occurring in trans with a known pathogenic MSH2 variant in a patient with colorectal cancer after age 45 and without CMMRD features has been reported. Details ▾Hide ▴
Evidence considered
- No co-occurrence in trans reported
Still missing
- No trans co-occurrence data
Sources
BS3 No calibrated functional assay demonstrating normal function has been performed for this variant. While SpliceAI predicts no splicing impact (delta 0.04), in silico predictions alone do not satisfy the VCEP BS3 requirement for a laboratory-based mRNA or protein assay. No mRNA aberration study with NMD inhibition has been conducted. Details ▾Hide ▴
Evidence considered
- SpliceAI predicts no splicing impact — insufficient alone for BS3
- No laboratory mRNA assay performed
- Variant not listed in VCEP functional assay documentation
Still missing
- No laboratory splicing or protein assay data
Sources
spliceai ↗vcep_functional_assay_svi_documentation_mmr
BS4 No segregation or lack-of-segregation data have been reported for this variant in affected families. Details ▾Hide ▴
Evidence considered
- No segregation data available
Still missing
- No family segregation studies
Sources
BP5 No tumor data (MSS status, IHC protein expression, BRAF V600E, or MLH1 methylation) are reported for patients carrying this variant. The VCEP BP5 rules require tumor evidence inconsistent with LS or pointing to a sporadic etiology. Details ▾Hide ▴
Evidence considered
- No tumor phenotype data available
Still missing
- No tumor MSS/IHC data
Sources
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PS4 VCEPThe InSiGHT MSH2 VCEP v2.0.0 marks PS4 as Not Applicable. Details ▾Hide ▴
PM1 VCEPThe InSiGHT MSH2 VCEP v2.0.0 marks PM1 as Not Applicable. Details ▾Hide ▴
PM5 N/APM5 requires a missense change at an amino acid residue where a different missense change has been classified as Pathogenic or Likely Pathogenic. This is an intronic variant (c.2458+8C>G) and does not alter an amino acid. Details ▾Hide ▴
Evidence considered
- Intronic variant
- not a missense substitution
PM6 VCEPThe InSiGHT MSH2 VCEP v2.0.0 marks PM6 as Not Applicable. Details ▾Hide ▴
PP2 VCEPThe InSiGHT MSH2 VCEP v2.0.0 marks PP2 as Not Applicable. Details ▾Hide ▴
PP5 VCEPThe InSiGHT MSH2 VCEP v2.0.0 marks PP5 as Not Applicable. Details ▾Hide ▴
BP1 VCEPThe InSiGHT MSH2 VCEP v2.0.0 marks BP1 as Not Applicable. Details ▾Hide ▴
BP2 VCEPThe InSiGHT MSH2 VCEP v2.0.0 marks BP2 as Not Applicable (BS2 is used instead). Details ▾Hide ▴
BP6 VCEPThe InSiGHT MSH2 VCEP v2.0.0 marks BP6 as Not Applicable for this VCEP, as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
PS5 N/APS5 is not defined in the InSiGHT MSH2 VCEP v2.0.0 criteria set. PP5 is also marked Not Applicable by the VCEP. There is no expert panel classification of this variant as pathogenic, and no reputable source has classified it as pathogenic independent of evaluable evidence. Details ▾Hide ▴
Evidence considered
- Criterion not defined in VCEP framework
- PP5 marked Not Applicable by VCEP
Sources
Identifiers
- Gene
- MSH2
- Transcript
- NM_000251.3
- Coding (HGVS c.)
- NM_000251.3:c.2458+8C>G
- Protein (HGVS p.)
- NP_000242.1:p.?
- GRCh38
- chr2:47478527 C>G
- GRCh37
- chr2:47705666 C>G
- ClinVar
- 135857
- COSMIC
- COSV105858622
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
33 / 1,613,836 alleles
AF 2.04e-05 · 0 homozygotes · FAF 8.99e-05
gnomAD v2.1
17 / 282,494 alleles
AF 6.02e-05 · 0 homozygotes · FAF 0.000135
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 2e-05 · 33 / 1,613,836 alleles · 0 hom · FAF 9e-05
| Admixed American10 / 60,030 | 0.00017 |
| East Asian2 / 44,860 | 4.5e-05 |
| Remaining individuals2 / 62,500 | 3.2e-05 |
| European (non-Finnish)19 / 1,179,892 | 1.6e-05 |
0 alternate alleles recorded in 6 other groups: European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 6e-05 · 17 / 282,494 alleles · 0 hom · FAF 0.00013
| Admixed American9 / 35,402 | 0.00025 |
| Remaining individuals1 / 7,210 | 0.00014 |
| East Asian1 / 19,950 | 5e-05 |
| European (non-Finnish)6 / 129,024 | 4.7e-05 |
0 alternate alleles recorded in 4 other groups: African/African American, Ashkenazi Jewish, European (Finnish), South Asian.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.04482e-05; MAF= 0.00204%, 33/1613836 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000166583; MAF= 0.01666%, 10/60030 alleles, homozygotes = 0); grpmax FAF= 8.993e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.01783e-05; MAF= 0.00602%, 17/282494 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000254223; MAF= 0.02542%, 9/35402 alleles, homozygotes = 0); grpmax FAF= 0.00013492.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingThe VCEP BP4 rule for intronic variants states: SpliceAI predicts no splicing impact with delta score ≤ 0.1. The SpliceAI max delta score for this variant is 0.04, satisfying this criterion at the Supporting strength level. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.04 ≤ 0.1 — no predicted splicing impact
Sources
BP7 SupportingThe VCEP BP7 rule states that synonymous or intronic variants at or beyond −21/+7 (5′/3′ exonic) meet BP7 at Supporting strength. This variant is at position c.2458+8, which is beyond the +7 threshold. Details ▾Hide ▴
PP3 The VCEP PP3 rules for non-canonical splice variants require a SpliceAI delta score ≥ 0.2 for supporting-level evidence. SpliceAI max delta score for this variant is 0.04, well below the threshold. The HCI prior missense path is inapplicable as this is an intronic variant. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.04 — below 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 = 0.04).
9 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. · 2005No paper-specific finding is recorded.
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PMID 25070057 ↗Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer.No paper-specific finding is recorded.
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PMID 25645574 ↗ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.No paper-specific finding is recorded.
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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.No paper-specific finding is recorded.
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PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.No paper-specific finding is recorded.
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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. · 2001No paper-specific finding is recorded.
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PMID 15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.Trepanier A et al. · 2004No paper-specific finding is recorded.
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PMID 20065170 ↗American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility.Robson ME et al. · 2010No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.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
33 / 1,613,836 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.040
Open source ↗
ClinVar
10 Likely benign · 1 benign · 1 Likely Benign · 1 Benign
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/135857/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-47705666-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47478527-C-G?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000251.3%3Ac.2458…
- OncoKB ↗www.oncokb.org/gene/MSH2/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=124532127
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= 2.04482e-05; MAF= 0.00204%, 33/1613836 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000166583; MAF= 0.01666%, 10/60030 alleles, homozygotes = 0); grpmax FAF= 8.993e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.01783e-05; MAF= 0.00602%, 17/282494 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000254223; MAF= 0.02542%, 9/35402 alleles, homozygotes = 0); grpmax FAF= 0.00013492.
ClinVar
This variant has been reported in ClinVar as Likely benign (10 clinical laboratories) and as benign (1 clinical laboratory) and as Likely Benign (1 clinical laboratory) and as Benign (1 clinical laboratory). (ClinVarID = 135857)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).
Somatic
This variant has previously been reported in somatic cancers (COSMIC; COSV105858622, n = 1 times).