Variant classification summary

NM_000251.3:c.1147C>T

MSH2 · NP_000242.1:p.(Arg383Ter) · NM_000251.3

GRCh37: chr2:47656951 C>T · GRCh38: chr2:47429812 C>T

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.(Arg383Ter)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The MSH2 NM_000251.3:c.1147C>T (p.Arg383Ter; p.R383*) variant has been reported in ClinVar and includes an expert panel Pathogenic classification.

2

This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 2/1614058 alleles (AF 1.23911e-06; 0.00012%), which is below the MSH2 PM2 threshold of 0.00002.

3

This nonsense variant introduces a premature stop at codon 383, which is well upstream of the MSH2 codon 891 cutoff for very strong PVS1 evidence and is consistent with loss of function as an established disease mechanism for MSH2-related disease.

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 is a nonsense change, NM_000251.3:c.1147C>T (p.Arg383Ter; p.R383*), in MSH2. Under the MSH2-specific ClinGen InSiGHT specification, nonsense variants introducing a premature termination codon at or before codon 891 meet PVS1 at very strong strength; this stop occurs at codon 383, well upstream of that threshold and is consistent with loss of function as an established disease mechanism.	cspec pvs1_gene_context pvs1_variant_assessment vcep_pvs1_decisiontree_mmr
PM2	Met	This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 2/1614058 alleles (AF 1.23911e-06; 0.00012%) with no homozygotes. This frequency is below the MSH2 PM2 threshold of 0.00002 (1 in 50,000 alleles), supporting PM2.	gnomad_v2 gnomad_v4 cspec
BA1	Not met	This variant does not meet BA1 because the gnomAD v4.1 allele frequency is 1.23911e-06, which is far below the BA1 threshold of 0.001 (0.1%).	gnomad_v4 cspec
BS1	Not met	This variant does not meet BS1 because the gnomAD v4.1 allele frequency is 1.23911e-06, which is well below the BS1 threshold of 0.0001 (0.01%).	gnomad_v4 cspec
PP4	Not assessed	No tumor microsatellite instability result, mismatch repair immunohistochemistry result, or other phenotype data were identified to determine whether the clinical findings meet the MSH2-specific PP4 criteria.	cspec vcep_table_for_cmmrd_diagnosis
BS4	Not assessed	No segregation data were identified showing lack of co-segregation with disease, so BS4 cannot be assessed.	cspec
BS3	Not assessed	No variant-specific calibrated functional assay or RNA study demonstrating retained function or no mRNA abnormality was identified, so BS3 cannot be applied.	vcep_functional_assay_flowchart vcep_functional_assay_svi_documentation_mmr
PM5	N/A	PM5 is not applicable because this is a nonsense variant, not a missense substitution at a residue with another established pathogenic or likely pathogenic missense change.	cspec
BP4	N/A	BP4 is not applicable because the MSH2 specification uses this criterion for missense variants with low HCI prior probability or for synonymous/intronic variants with SpliceAI <=0.1. This variant is a nonsense substitution. A BayesDel score of 0.66 was available, but this does not establish BP4 for this variant type under the active MSH2 rules.	cspec bayesdel
PS1	N/A	PS1 is not applicable because this criterion is defined here for predicted missense substitutions encoding the same amino acid change, or for non-canonical splice variants affecting the same nucleotide as an established splice variant. This variant is a nonsense substitution.	cspec
PS2	Not assessed	No de novo data were identified for this variant, so PS2 cannot be assessed.	cspec
PP1	Not assessed	No co-segregation data were identified for this variant, so PP1 cannot be assessed.	cspec
BP5	Not assessed	No tumor data were identified showing mismatch repair findings inconsistent with MSH2 involvement, so BP5 cannot be assessed.	cspec
PVS1_generic_framework	N/A	A gene-specific MSH2 PVS1 rule is available and was used, so the generic PVS1 framework is not the primary adjudication rule for this case.	cspec pvs1_generic_framework
PS3	Not assessed	No variant-specific calibrated functional assay or RNA study demonstrating a damaging effect under the approved MMR assay framework was identified, so PS3 cannot be applied.	vcep_functional_assay_flowchart vcep_functional_assay_svi_documentation_mmr
PP3	N/A	PP3 is not applicable because the MSH2 specification uses this criterion for missense variants with elevated HCI prior probability or for non-canonical splice variants with SpliceAI >=0.2. This variant is a nonsense substitution. No HCI prior or REVEL score was available, and the available BayesDel score does not establish PP3 for this variant type under the active MSH2 rules.	cspec bayesdel vcep_hci_priors_msh2
BS2	Not assessed	No confirmed in trans co-occurrence data with a pathogenic MSH2 variant in an individual without features of constitutional mismatch repair deficiency were identified, so BS2 cannot be assessed.	cspec vcep_table_for_cmmrd_diagnosis
PM3	Not assessed	No biallelic observation or points-based recessive evidence was identified for this variant, so PM3 cannot be assessed.	cspec
BP7	N/A	BP7 is not applicable because this variant is not synonymous or intronic.	cspec
BP3	N/A	BP3 is not applicable under the MSH2 specification.	cspec
BP2	N/A	BP2 is not applicable under the MSH2 specification.	cspec
BP6	N/A	BP6 is not applicable under the MSH2 specification.	cspec
PM1	N/A	PM1 is not applicable under the MSH2 specification.	cspec vcep_mmr_functional_domains
PP5	Met	Expert panel International Society for Gastrointestinal Hereditary Tumours (InSiGHT) classified as Pathogenic.	cspec clinvar
PM6	N/A	PM6 is not applicable under the MSH2 specification.	cspec
PS4	N/A	PS4 is not applicable under the MSH2 specification.	cspec
PM4	N/A	PM4 is not applicable under the MSH2 specification.	cspec
BP1	N/A	BP1 is not applicable under the MSH2 specification.	cspec
PP2	N/A	PP2 is not applicable under the MSH2 specification.	cspec

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