Variant classification summary

NM_000251.3:c.793-11_794dup

MSH2 · NP_000242.1:p.? · NM_000251.3

GRCh37: chr2:47641395 T>TTCTTAATTTTAGG · GRCh38: chr2:47414256 T>TTCTTAATTTTAGG

Gene: MSH2 Transcript: NM_000251.3

Final call

VUS

PM2_Supporting PP3_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

1

The MSH2 c.793-11_794dup (NP_000242.1:p.?) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1; in gnomAD v4.1 the observed allele frequency is 0, which is below the MSH2 PM2_Supporting threshold of less than 0.00002.

3

SpliceAI predicts a splice effect with a maximum delta score of 0.71, which is above the MSH2 PP3 threshold of 0.2 for non-canonical splice variants and above the BP4 no-impact threshold of 0.1.

Final determination: PM2_Supporting and PP3_Supporting provide two supporting pathogenic criteria, which do not meet any Pathogenic or Likely Pathogenic combination rule in the official MSH2/InSiGHT framework; therefore the variant is classified as of uncertain significance.

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
PP4	Not assessed	No colorectal or endometrial tumor MSI result, tumor genome result, or mismatch repair immunohistochemistry result was identified, so the MSH2-specific PP4 tumor criteria cannot be evaluated.	case_summary.compact_evidence literature_pass.json
BP3	N/A	BP3 is not used by the MSH2 VCEP for variant interpretation.	MSH2/criteria.json
BP7	Not met	This intronic duplication is located at c.793-11_794dup, which is 11 nucleotides upstream of the exon boundary. This does not meet the MSH2 BP7 positional requirement of at or beyond -21 in the intron.	prefetch.normalize.variant_validator MSH2/criteria.json
BS4	Not assessed	No segregation studies or Bayes likelihood ratio data were identified, so lack of segregation with disease cannot be assessed.	case_summary.json literature_pass.json
BS3	Not assessed	No RNA study showing no splicing abnormality and no calibrated functional assay showing benign function were identified, so BS3 cannot be applied.	vcep_materials.json literature_pass.json MSH2/criteria.json
PM5	N/A	PM5 applies to missense substitutions at an amino acid residue with a different established pathogenic missense change. This variant is an intronic duplication and does not encode a missense substitution.	case_summary.normalization MSH2/criteria.json
BP2	N/A	BP2 is not used by the MSH2 VCEP; BS2 is used instead for relevant co-occurrence evidence.	MSH2/criteria.json
PM2	Met	This variant is absent from gnomAD v4.1, which is below the MSH2 PM2_Supporting threshold of less than 0.00002 (less than 1 in 50,000 alleles).	evidence.json.results.gnomad.GNOMAD_V4_1 evidence.json.results.gnomad.GNOMAD_V2_1 MSH2/criteria.json
BP4	Not met	For intronic variants, BP4 requires SpliceAI to predict no splicing impact with a delta score of 0.1 or less. This variant has a maximum SpliceAI delta score of 0.71, which is above that threshold and does not support BP4.	evidence.json.results.spliceai case_summary.compact_evidence.spliceai MSH2/criteria.json
BP6	N/A	BP6 is not used by this VCEP.	MSH2/criteria.json
PS1	Not met	PS1 for non-canonical splice variants requires a previously established pathogenic or likely pathogenic variant affecting the same splice nucleotide with similar or worse splicing prediction. No such same-nucleotide precedent was identified for this variant.	MSH2/criteria.json literature_pass.json evidence.json.results.clinvar
PS2	Not assessed	No de novo data, parental confirmation, or tumor evidence consistent with MSH2 deficiency were identified, so PS2 cannot be assessed.	case_summary.json literature_pass.json MSH2/criteria.json
BS1	Not met	BS1 requires a gnomAD v4 group maximum filtering allele frequency of at least 0.0001 and less than 0.001. This variant is absent from gnomAD v4.1, so its frequency is below the BS1 threshold.	evidence.json.results.gnomad.GNOMAD_V4_1 MSH2/criteria.json
PM1	N/A	PM1 is not used for MSH2 because the VCEP does not recognize mutational hot spots suitable for classification purposes.	MSH2/criteria.json vcep_materials.json
PP5	N/A	PP5 is not used by this VCEP.	MSH2/criteria.json
PP1	Not assessed	No family segregation data or Bayes likelihood ratio were identified, so co-segregation with disease cannot be assessed.	case_summary.json literature_pass.json MSH2/criteria.json
BP5	Not assessed	No tumor profile inconsistent with MSH2-associated disease and no alternate molecular explanation for the phenotype were identified, so BP5 cannot be assessed.	case_summary.json literature_pass.json MSH2/criteria.json
PM6	N/A	PM6 is marked not applicable by the MSH2 VCEP.	MSH2/criteria.json
BA1	Not met	BA1 requires a gnomAD v4 group maximum filtering allele frequency of at least 0.001. This variant is absent from gnomAD v4.1, so it is below the BA1 threshold.	evidence.json.results.gnomad.GNOMAD_V4_1 MSH2/criteria.json
PVS1	Not met	This variant is a non-canonical intronic duplication at c.793-11_794dup and is not a canonical +/-1,2 splice variant, nonsense variant, frameshift variant, or exon-level duplication. SpliceAI predicts a possible splice effect with a maximum delta score of 0.71, but no constitutional RNA assay demonstrating a splice aberration with loss of the full-length transcript was identified, so current evidence does not meet the MSH2 VCEP PVS1 rule.	pvs1_gene_context.json pvs1_variant_assessment.json evidence.json.results.spliceai MSH2/criteria.json
PS4	N/A	PS4 is not used by the MSH2 VCEP because tumor evidence is incorporated through PP4 instead.	MSH2/criteria.json
PM4	N/A	PM4 is not used by the MSH2 VCEP for protein length changes from in-frame variants.	MSH2/criteria.json
PS3	Not assessed	No variant-specific calibrated functional assay, constitutional RNA assay showing a damaging splice defect, or monoallelic expression data were identified, so PS3 cannot be applied.	vcep_materials.json literature_pass.json MSH2/criteria.json
PP3	Met	SpliceAI predicts a splice defect with a maximum delta score of 0.71, which is above the MSH2 PP3 threshold of 0.2 for non-canonical splice nucleotides and supports a predicted splicing impact.	evidence.json.results.spliceai case_summary.compact_evidence.spliceai MSH2/criteria.json
BS2	Not assessed	No evidence was identified showing this variant in trans with a known pathogenic MSH2 variant in an individual whose clinical features argue against constitutional mismatch repair deficiency, so BS2 cannot be assessed.	case_summary.json literature_pass.json MSH2/criteria.json vcep_materials.json
BP1	N/A	BP1 is not used by the MSH2 VCEP.	MSH2/criteria.json
PM3	Not assessed	No evidence was identified showing this variant in trans with a pathogenic or likely pathogenic MSH2 variant in an individual with clinical features consistent with constitutional mismatch repair deficiency, so PM3 cannot be assessed.	case_summary.json literature_pass.json MSH2/criteria.json vcep_materials.json
PP2	N/A	PP2 is not used by the MSH2 VCEP.	MSH2/criteria.json

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.