NM_000251.3:c.1661+1G>A

MSH2 · NP_000242.1:p.? · NM_000251.3

GRCh37: chr2:47693948 G>A · GRCh38: chr2:47466809 G>A

Gene: MSH2 Transcript: NM_000251.3

Final call

Pathogenic

PVS1 very strong PM2 supporting PP5 supporting

Variant details

Gene

MSH2

Transcript

NM_000251.3

Protein

NP_000242.1:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

The MSH2 NM_000251.3:c.1661+1G>A (NP_000242.1:p.?) variant has been reported in ClinVar, including an InSiGHT expert panel classification of likely pathogenic and additional pathogenic/likely pathogenic clinical laboratory submissions.

This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 (1/1,612,780 alleles; AF 6.20e-07), which is below the MSH2 VCEP PM2 threshold of 0.00002.

SpliceAI predicts a strong splice effect for this canonical donor variant (max delta score 0.97), supporting predicted disruption of normal splicing; however, this computational evidence was not counted separately because the same splice effect is captured under PVS1 for a canonical +1 splice-site variant.

Final determination: Rule4 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 Pathogenic.

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	Met	This variant affects the canonical +1 donor splice nucleotide in MSH2. Under the MSH2 InSiGHT specification, canonical ±1,2 splice variants can meet PVS1 at very strong strength when loss of function is an established disease mechanism and the predicted splice consequence is expected to create a null transcript; the available MSH2 PVS1 assessments support full-strength application for this variant. PP3 was not added because the same predicted splice effect should not be double-counted.	cspec pvs1_gene_context pvs1_variant_assessment vcep_pvs1_decisiontree_mmr
PM2	Met	This variant is absent from gnomAD v2.1 and present only once in gnomAD v4.1 (1/1,612,780 alleles; AF 6.20e-07, 0 homozygotes), which is below the MSH2 VCEP PM2 threshold of 0.00002 (1 in 50,000 alleles). This supports PM2 at supporting strength.	cspec gnomad_v2 gnomad_v4
PP3	N/A	SpliceAI predicts a strong splice effect for this variant (max delta score 0.97), but the MSH2 VCEP PP3 splice rule applies to non-canonical splicing nucleotides. This is a canonical +1 splice-site variant, and the same splice prediction evidence should not be stacked with PVS1.	cspec spliceai bayesdel pvs1_variant_assessment
BP4	Not met	Available computational evidence does not support no splice impact. SpliceAI predicts a strong splice effect for this intronic variant (max delta score 0.97), which is well above the MSH2 VCEP BP4 threshold of 0.1 for intronic variants predicted to have no splicing impact. A BayesDel score of 0.66 is available, but the VCEP intronic computational rule is based on SpliceAI.	cspec spliceai bayesdel
BS1	Not met	The population frequency does not reach the benign strong threshold. In gnomAD v4.1 this variant is present at 1/1,612,780 alleles (AF 6.20e-07), which is below the BS1 threshold of 0.0001.	cspec gnomad_v4
BA1	Not met	The population frequency does not reach the benign stand-alone threshold. In gnomAD v4.1 this variant is present at 1/1,612,780 alleles (AF 6.20e-07), which is below the BA1 threshold of 0.001.	cspec gnomad_v4
PS3	Not assessed	No validated variant-specific functional or RNA assay result was confirmed for this exact variant from the available evidence. Although splice studies are relevant for MMR splice-site variants, no direct assay result was verified here to support PS3.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart
BS3	Not assessed	No well-established study showing normal splicing or preserved MSH2 function for this exact variant was confirmed. The available evidence does not support BS3.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart
PP4	Not assessed	No tumor microsatellite instability result, mismatch repair immunohistochemistry result, or other phenotype data were identified to determine whether the MSH2 VCEP PP4 phenotype thresholds are met.	cspec vcep_table_for_cmmrd_diagnosis
PP1	Not assessed	No segregation data were identified to calculate a Bayes likelihood ratio for co-segregation with disease. The available evidence does not support PP1 at this time.	cspec
BS4	Not assessed	No non-segregation data were identified to calculate a Bayes likelihood ratio arguing against pathogenicity. The available evidence does not support BS4 at this time.	cspec
PS2	Not assessed	No confirmed de novo occurrence was identified for this variant. The available evidence does not support PS2.	cspec
PM3	Not assessed	No evidence was identified that this variant occurred in trans with a pathogenic MSH2 variant in a case informative for CMMRD scoring. The available evidence does not support PM3.	cspec vcep_table_for_cmmrd_diagnosis
BS2	Not assessed	No confirmed observation in trans with a known pathogenic MSH2 variant in a person whose clinical features argue against CMMRD was identified. The available evidence does not support BS2.	cspec vcep_table_for_cmmrd_diagnosis
BP5	Not assessed	No tumor findings were identified that are inconsistent with MSH2-related mismatch repair deficiency. The available evidence is insufficient to assess BP5.	cspec
PS1	N/A	This criterion is designed for predicted missense substitutions or non-canonical splice nucleotides matched to previously established splice variants. This variant is a canonical +1 splice donor change, so PS1 is not applicable.	cspec
PM5	N/A	PM5 applies to missense variants at amino acid residues with established pathogenic or likely pathogenic missense substitutions. This is not a missense variant.	cspec
BP7	N/A	BP7 applies to synonymous or deep intronic variants at or beyond -21/+7. This variant is at the canonical +1 splice donor nucleotide, so BP7 is not applicable.	cspec
BP3	N/A	BP3 is not used in this VCEP framework and is not applicable to this variant.	cspec
BP2	N/A	BP2 is not used in this VCEP framework; BS2 is used instead when relevant.	cspec
BP6	N/A	BP6 is not for use in this VCEP framework.	cspec
PM1	N/A	PM1 is not applicable in this VCEP framework for this variant.	cspec
PP5	Met	Expert panel International Society for Gastrointestinal Hereditary Tumours (InSiGHT) classified as Likely pathogenic.	cspec clinvar
PM6	N/A	PM6 is not applicable in this VCEP framework.	cspec
PS4	N/A	PS4 is not applicable in this VCEP framework.	cspec
PM4	N/A	PM4 is not applicable in this VCEP framework.	cspec
BP1	N/A	BP1 is not applicable in this VCEP framework.	cspec
PP2	N/A	PP2 is not applicable in this VCEP framework.	cspec

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