Variant classification summary

NM_000251.3:c.2458+8C>G

MSH2 · NP_000242.1:p.? · NM_000251.3

GRCh37: chr2:47705666 C>G · GRCh38: chr2:47478527 C>G

Gene: MSH2 Transcript: NM_000251.3

Final call

Likely Benign

BP4 supporting benign BP7 supporting benign

Variant details

Gene

MSH2

Transcript

NM_000251.3

Protein

NP_000242.1:p.?

gnomAD AF

2.0448174411774182e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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.

3

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.

4

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.

5

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).

6

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).

Final determination: Rule19 in the Richards et.al., 2015 - Combining rules v2.0.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Likely Benign.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not met	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.	spliceai pvs1_generic_framework
PS1	Not met	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.
PS2	Not met	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.	clinvar
PS3	Not met	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.	vcep_functional_assay_svi_documentation_mmr
PS4	N/A	The InSiGHT MSH2 VCEP v2.0.0 marks PS4 as Not Applicable.	cspec
PS5	N/A	PS5 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.	cspec
PM1	N/A	The InSiGHT MSH2 VCEP v2.0.0 marks PM1 as Not Applicable.	cspec
PM2	Not met	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.	gnomad_v4
PM5	N/A	PM5 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.
PM6	N/A	The InSiGHT MSH2 VCEP v2.0.0 marks PM6 as Not Applicable.	cspec
PP1	Not met	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.	clinvar
PP2	N/A	The InSiGHT MSH2 VCEP v2.0.0 marks PP2 as Not Applicable.	cspec
PP3	Not met	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.	spliceai
PP4	Not met	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.	clinvar
PP5	N/A	The InSiGHT MSH2 VCEP v2.0.0 marks PP5 as Not Applicable.	cspec
BA1	Not met	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.	gnomad_v4
BS1	Not met	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.	gnomad_v4
BS2	Not met	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.	clinvar
BS3	Not met	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.	spliceai vcep_functional_assay_svi_documentation_mmr
BS4	Not met	No segregation or lack-of-segregation data have been reported for this variant in affected families.	clinvar
BP1	N/A	The InSiGHT MSH2 VCEP v2.0.0 marks BP1 as Not Applicable.	cspec
BP2	N/A	The InSiGHT MSH2 VCEP v2.0.0 marks BP2 as Not Applicable (BS2 is used instead).	cspec
BP4	Met	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 cspec
BP5	Not met	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.	clinvar
BP6	N/A	The 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.	cspec
BP7	Met	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.	cspec

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