NM_000251.3:c.2034T>A

MSH2 · NP_000242.1:p.(Tyr678Ter) · NM_000251.3

GRCh37: chr2:47703534 T>A · GRCh38: chr2:47476395 T>A

Gene: MSH2 Transcript: NM_000251.3

Final call

VUS

PVS1 very strong PM2 supporting

Variant details

Gene

MSH2

Transcript

NM_000251.3

Protein

NP_000242.1:p.(Tyr678Ter)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The MSH2 c.2034T>A (p.Tyr678Ter; p.Y678*) variant has been reported in ClinVar as pathogenic by 2 clinical laboratories.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the MSH2 VCEP PM2 threshold of less than 0.00002 in gnomAD v4.

This nonsense variant introduces a premature stop codon at Tyr678; under the MSH2 VCEP specification, nonsense variants at or before codon 891 meet PVS1, and p.(Tyr678Ter) falls within that range.

SpliceAI predicts no significant splice impact for this variant (max delta score 0.01), which is consistent with premature protein truncation rather than a predicted splice defect.

Final determination: No criteria-combination rule matched the adjudicated criteria in the Richards et.al., 2015 - Combining rules v2.0.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

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 is a nonsense change predicted to create p.(Tyr678Ter). Under the MSH2 VCEP specification, nonsense variants introducing a premature stop codon at or before codon 891 meet PVS1; this stop occurs at codon 678 and supports loss of function as the disease mechanism.	cspec pvs1_gene_context pvs1_variant_assessment
PM2	Met	This variant is absent from gnomAD v4.1 and gnomAD v2.1. Absence from gnomAD v4.1 is below the MSH2 VCEP PM2 threshold of less than 0.00002 and supports PM2 at supporting strength.	gnomad_v4 gnomad_v2 cspec
PP4	Not assessed	No tumor microsatellite instability result, mismatch repair immunohistochemistry pattern, or other phenotype data were identified to determine whether the MSH2 VCEP PP4 thresholds are met.	cspec
BP3	N/A	BP3 is not used in the MSH2 VCEP framework.	cspec
BP7	N/A	BP7 applies to synonymous or qualifying intronic variants. This variant is a nonsense substitution, so BP7 does not apply.	cspec spliceai
BS4	Not assessed	No segregation study or Bayes likelihood ratio was identified showing lack of co-segregation with disease.	cspec
BS3	Not assessed	No calibrated variant-specific functional assay or constitutional RNA study demonstrating a benign effect was identified for this variant, so BS3 cannot be applied.	cspec vcep_functional_assay_flowchart vcep_functional_assay_svi_documentation_mmr
PM5	N/A	The MSH2 VCEP uses classic same-residue PM5 logic for missense variants. This variant is a nonsense change, so PM5 does not apply.	cspec pm5_candidates
BP2	N/A	BP2 is not used in the MSH2 VCEP framework.	cspec
BP4	N/A	MSH2 VCEP BP4 applies to missense variants with an HCI prior below 0.11 or to qualifying intronic/synonymous variants with SpliceAI less than or equal to 0.1. This variant is a nonsense change, so BP4 does not apply.	cspec spliceai bayesdel vcep_hci_priors_msh2
BP6	N/A	BP6 is not used in the MSH2 VCEP framework.	cspec
PS1	N/A	MSH2 VCEP PS1 applies to predicted missense substitutions encoding the same amino acid change, or to specific non-canonical splice nucleotide comparisons. This variant is a nonsense change, so PS1 does not apply.	cspec
PS2	Not assessed	No de novo occurrence with confirmed parentage was identified for this variant.	cspec
BS1	Not met	This variant is absent from gnomAD v4.1 and therefore does not reach the BS1 threshold of at least 0.0001.	gnomad_v4 cspec
PM1	N/A	PM1 is not used in the MSH2 VCEP framework.	cspec
PP5	N/A	PP5 is not used in the MSH2 VCEP framework.	cspec
PP1	Not assessed	No pedigree data were identified showing co-segregation of this variant with Lynch syndrome-related disease.	cspec
BP5	Not assessed	No tumor data were identified showing microsatellite stable tumors, intact mismatch repair protein expression, or an inconsistent mismatch repair loss pattern that would support BP5.	cspec
PM6	N/A	PM6 is not used in the MSH2 VCEP framework.	cspec
BA1	Not met	This variant is absent from gnomAD v4.1 and therefore does not reach the BA1 threshold of at least 0.001.	gnomad_v4 cspec
PS4	N/A	PS4 is not used in the MSH2 VCEP framework.	cspec
PM4	N/A	PM4 is not used in the MSH2 VCEP framework.	cspec
PS3	Not assessed	No calibrated variant-specific functional assay or constitutional RNA study demonstrating a damaging effect was identified for this variant, so PS3 cannot be applied independently of PVS1.	cspec vcep_functional_assay_flowchart vcep_functional_assay_svi_documentation_mmr
PP3	N/A	MSH2 VCEP PP3 applies to missense variants with qualifying HCI prior values or to non-canonical splice variants with SpliceAI delta score at least 0.2. This variant is a nonsense change, and SpliceAI predicts no significant splice impact (max delta score 0.01), so PP3 does not apply.	cspec spliceai vcep_hci_priors_msh2
BS2	Not assessed	No phase-confirmed observation of this variant in trans with a known pathogenic MSH2 variant in a person without clinical evidence of constitutional mismatch repair deficiency was identified.	cspec vcep_table_for_cmmrd_diagnosis
BP1	N/A	BP1 is not used in the MSH2 VCEP framework.	cspec
PM3	Not assessed	No confirmed biallelic or in trans observation relevant to the MSH2 VCEP PM3 scoring system was identified for this variant.	cspec vcep_table_for_cmmrd_diagnosis
PP2	N/A	PP2 is not used in the MSH2 VCEP framework.	cspec

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.