Variant classification summary

NM_000251.3:c.198C>A

MSH2 · NP_000242.1:p.(Tyr66Ter) · NM_000251.3

GRCh37: chr2:47630528 C>A · GRCh38: chr2:47403389 C>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.(Tyr66Ter)

gnomAD AF

0.0 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1_VeryStrong is met: c.198C>A (p.Tyr66Ter) is a nonsense variant introducing a premature termination codon at codon 66, which is ≤ codon 891 in MSH2, satisfying the InSiGHT MSH2 v2.0.0 VCEP PVS1 rule for full-strength PVS1.

2

PM2_Supporting is met: the variant is absent from gnomAD v4.1 (0/1,601,554 alleles) and gnomAD v2.1, satisfying the VCEP PM2_Supporting threshold of <0.00002 (<1 in 50,000 alleles).

3

Under the InSiGHT MSH2 v2.0.0 VCEP combination rules (Richards et al. 2015 framework), the combination of 1 Pathogenic Very Strong (PVS1) and 1 Pathogenic Supporting (PM2) does not satisfy any rule for Pathogenic or Likely Pathogenic classification. A minimum of 1 Very Strong + 2 Supporting, or 1 Very Strong + 1 Moderate would be required for Pathogenic or Likely Pathogenic, respectively. The variant is classified as Variant of Uncertain Significance (VUS) per the VCEP combination rule set.

4

This variant has been reported as Pathogenic by 6 clinical laboratories in ClinVar (VariationID: 645593). However, the VCEP does not recognize PP5/ClinVar consensus as an applicable criterion, and no expert panel classification has been issued for this variant.

5

No variant-specific functional (PS3/BS3), segregation (PP1/BS4), tumor phenotype (PP4/BP5), or de novo (PS2) data were identified for this variant in any reviewed source. Full-text publications retrieved for relevant PMIDs (24362816, 10946232, 11257106, 15528792, 23391514) did not contain accessible article content — all returned Sci-Hub landing page artifacts without variant-specific evidence.

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	Nonsense variant NM_000251.3:c.198C>A (p.Tyr66Ter) introduces a premature termination codon at codon 66, which is ≤ codon 891 in MSH2, satisfying the VCEP InSiGHT MSH2 v2.0.0 PVS1_VeryStrong rule. Loss of function is an established disease mechanism for MSH2 in Lynch syndrome as confirmed by the ClinGen InSiGHT CSPEC framework.	cspec pvs1_variant_assessment pvs1_gene_context
PS1	N/A	PS1 requires a missense substitution encoding the same amino acid change with a different nucleotide change, or variants affecting the same non-canonical splice nucleotide. c.198C>A is a nonsense variant, not a missense or splice variant.
PS2	Not assessed	No de novo data available for this variant. The VCEP InSiGHT MSH2 v2.0.0 PS2 de novo point system requires specific parent-offspring testing data, which has not been identified in any reviewed source.
PS3	Not assessed	No variant-specific calibrated functional assay data available. The VCEP InSiGHT MSH2 v2.0.0 PS3 requires calibrated functional odds for pathogenicity > 2.08 from validated assays. While the VCEP functional assay spreadsheet catalogs calibrated assays (PMID:24362816, 30504929, etc.), none report functional data for p.Tyr66Ter specifically. As a nonsense variant, functional testing is typically not pursued since PVS1 already captures the expected null effect.	vcep_functional_assay_svi_documentation_mmr
PS4	N/A	VCEP InSiGHT MSH2 v2.0.0 lists PS4 as Not Applicable.	cspec
PS5	N/A	The VCEP InSiGHT MSH2 v2.0.0 does not include PS5 as an applicable criterion. PP5 (the analogous criterion in VCEP terminology) is explicitly listed as Not Applicable.	cspec
PM1	N/A	VCEP InSiGHT MSH2 v2.0.0 lists PM1 as Not Applicable.	cspec
PM2	Met	The variant is absent from gnomAD v4.1 (0/1,601,554 alleles, AF=0.00000%), satisfying the VCEP InSiGHT MSH2 v2.0.0 PM2_Supporting threshold of <0.00002 (<1 in 50,000 alleles). Also absent from gnomAD v2.1 and gnomAD-Canada v1.0.	gnomad_v4 gnomad_v2 cspec
PM5	N/A	PM5 requires a missense change at an amino acid residue where a different missense change was classified as P/LP. c.198C>A is a nonsense variant (p.Tyr66Ter), not a missense change.	pm5_candidates
PM6	N/A	VCEP InSiGHT MSH2 v2.0.0 lists PM6 as Not Applicable.	cspec
PP1	Not assessed	No co-segregation data available for this variant. The VCEP InSiGHT MSH2 v2.0.0 PP1 requires combined Bayes Likelihood Ratio from pedigree analysis. No segregation studies were identified in any reviewed source.
PP2	N/A	VCEP InSiGHT MSH2 v2.0.0 lists PP2 as Not Applicable.	cspec
PP3	N/A	VCEP InSiGHT MSH2 v2.0.0 PP3 applies only to missense variants (HCI prior probability >0.68) or non-canonical splice variants (SpliceAI delta ≥0.2). c.198C>A is a nonsense variant; the HCI priors table contains only missense substitutions and the variant is not found in it. SpliceAI delta score is 0.00, indicating no predicted splice impact.	cspec spliceai
PP4	Not assessed	No tumor phenotype data available for this variant. The VCEP InSiGHT MSH2 v2.0.0 PP4 requires MSI-H tumors or loss of MMR protein expression consistent with variant location. While PP4 was applied to some InSiGHT pilot variants, no MSI/IHC data specific to p.Tyr66Ter was identified in the evidence sources.	cspec
PP5	N/A	VCEP InSiGHT MSH2 v2.0.0 lists PP5 as Not Applicable.	cspec
BA1	Not met	VCEP InSiGHT MSH2 v2.0.0 BA1 requires gnomAD v4 Grpmax filtering allele frequency ≥0.001 (0.1%). The variant is absent from gnomAD v4.1 (0/1,601,554 alleles), so BA1 is not met.	gnomad_v4 cspec
BS1	Not met	VCEP InSiGHT MSH2 v2.0.0 BS1 requires gnomAD v4 Grpmax filtering allele frequency ≥0.0001 and <0.001 (0.01-0.1%). The variant is absent from gnomAD v4.1 (0/1,601,554 alleles), so BS1 is not met.	gnomad_v4 cspec
BS2	Not assessed	No data available for co-occurrence in trans with a known pathogenic MSH2 variant. The VCEP InSiGHT MSH2 v2.0.0 BS2 requires confirmed trans phase with a P/LP variant in a patient with CRC after age 45 without CMMRD features.
BS3	Not assessed	No variant-specific functional data demonstrating proficient MMR function. The VCEP InSiGHT MSH2 v2.0.0 BS3 requires calibrated functional assays with functional odds for pathogenicity ≤0.48, or proficient function in validated assays. As a nonsense variant introducing a stop codon at position 66, a null effect is expected and functional rescue data would be needed to support BS3.	vcep_functional_assay_svi_documentation_mmr
BS4	Not assessed	No segregation data available. The VCEP InSiGHT MSH2 v2.0.0 BS4 requires lack of co-segregation with disease in pedigrees with combined Bayes Likelihood Ratio <0.48.
BP1	N/A	VCEP InSiGHT MSH2 v2.0.0 lists BP1 as Not Applicable.	cspec
BP2	N/A	VCEP InSiGHT MSH2 v2.0.0 lists BP2 as Not Applicable.	cspec
BP4	N/A	VCEP InSiGHT MSH2 v2.0.0 BP4 applies only to missense variants (HCI prior <0.11) or intronic/synonymous variants (SpliceAI delta ≤0.1). c.198C>A is a nonsense variant. The HCI priors table does not contain nonsense variants.	cspec
BP5	Not assessed	No tumor phenotype data available. The VCEP InSiGHT MSH2 v2.0.0 BP5 requires MSS tumors, no loss of MMR protein expression, or LS spectrum tumors with inconsistent protein loss. No tumor data was identified for this variant.
BP6	N/A	VCEP InSiGHT MSH2 v2.0.0 lists BP6 as Not Applicable.	cspec
BP7	N/A	VCEP InSiGHT MSH2 v2.0.0 BP7 applies to synonymous (silent) or intronic variants at or beyond -21/+7. c.198C>A is a nonsense variant.	cspec

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