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 v2.0.0.1 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.2 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 BP4.3 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.4 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).5 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).6
MSH2
Final classification
Likely Benign
MSH2 c.2458+8C>G · p.?
MSH2
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.
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.
Classification rationale
BP4BP7
Likely Benign
MSH2 c.2458+8C>G
BP4 + BP7
→
Likely Benign
Gene diagram
· NM_000251.3 · variants mapped to exon structure
MSH2
NM_000251.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 14 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
BP4
supporting
Benign
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.
SpliceAI max delta score 0.04 ≤ 0.1 — no predicted splicing impact
✓
BP7
supporting
Benign
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.
Intronic variant at +8 positionbeyond the +7 exon boundary
Assessed · not applied
Pathogenic
PVS1
This is an intronic variant at position c.2458+8, outside the canonical splice donor/acceptor consensus (±1,2).
PS1
This intronic variant does not encode an amino acid change, so the missense-based PS1 path is inapplicable.
PS2
No de novo observations have been reported for this variant.
PS3
No calibrated functional assays have been performed on this variant.
PM2
The VCEP PM2 rule requires absent/extremely rare allele frequency <0.00002 (<1 in 50,000 alleles) in gnomAD v4.
PP1
No co-segregation data are available for this variant.
PP3
The VCEP PP3 rules for non-canonical splice variants require a SpliceAI delta score ≥ 0.2 for supporting-level evidence.
PP4
No tumor MSI/IHC data are reported for patients carrying this variant.
Benign
BA1
The VCEP BA1 rule requires gnomAD v4 grpmax filtering allele frequency ≥ 0.001 (0.1%).
BS1
The VCEP BS1 rule requires gnomAD v4 grpmax filtering allele frequency ≥ 0.0001 (0.01%) and < 0.001 (0.1%).
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.
BS3
No calibrated functional assay demonstrating normal function has been performed for this variant.
BS4
No segregation or lack-of-segregation data have been reported for this variant in affected families.
BP5
No tumor data (MSS status, IHC protein expression, BRAF V600E, or MLH1 methylation) are reported for patients carrying this variant.
N/A · 9
PS4 · PM1 · PM5 · PM6 · PP2 · PP5 · BP1 · BP2 · BP6
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
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.
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.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.002%
· 33 / 1,613,836
0 hom · FAF 0.009%
0 hom · FAF 0.009%
Admixed American 10 / 60,030 |
0.017% |
East Asian 2 / 44,860 |
0.0045% |
Remaining individuals 2 / 62,500 |
0.0032% |
European (non-Finnish) 19 / 1,179,892 |
0.0016% |
+ 6 not observed (European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.006%
· 17 / 282,494
0 hom · FAF 0.013%
0 hom · FAF 0.013%
Admixed American 9 / 35,402 |
0.025% |
Remaining individuals 1 / 7,210 |
0.014% |
East Asian 1 / 19,950 |
0.005% |
European (non-Finnish) 6 / 129,024 |
0.0047% |
+ 4 not observed (African/African American, Ashkenazi Jewish, European (Finnish), South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has previously been reported in somatic cancers (COSMIC; COSV105858622, n = 1 times).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links
Triaged references · 9 PMIDs not cited in assessment
15662714 ↗
Identification of Muir-Torre syndrome among patients with sebaceous tumors and keratoacanthomas: role of clinical features, microsatellite instability, and immunohistochemistry.
CLINVAR
25070057 ↗
Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer.
CLINVAR
25645574 ↗
ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.
CLINVAR
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.
CLINVAR
26467025 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
CLINVAR
11598466 ↗
Practice parameters for the identification and testing of patients at risk for dominantly inherited colorectal cancer--supporting documentation.
CLINVAR
15604628 ↗
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
CLINVAR
20065170 ↗
American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR