Variant classification summary

NM_000251.3:c.23C>G

MSH2 · NP_000242.1:p.(Thr8Arg) · NM_000251.3

GRCh37: chr2:47630353 C>G · GRCh38: chr2:47403214 C>G

Gene: MSH2 Transcript: NM_000251.3

Final call

PM2 supporting BP4 supporting

Variant details

Gene

MSH2

Transcript

NM_000251.3

Protein

NP_000242.1:p.(Thr8Arg)

gnomAD AF

1.8749812501874982e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

All three requested criteria are governed by the MSH2 InSiGHT VCEP framework; the variant is missense p.(Thr8Arg), PVS1 is outside the applicable loss-of-function classes, and PM4 and BP3 are explicitly Not Applicable.

2

The exact variant notations c.23C>G, p.Thr8Arg, and p.T8R were searched in both named governing full-text files; no exact entry was found.

3

For this criterion group, PS4, PP5, and BP6 are not applicable under the governing MSH2 InSiGHT VCEP rules.

4

PP4 and BP5 are applicable in principle but remain not assessed because the case lacks patient-specific tumor phenotype and alternate-molecular-basis data.

5

The exact variant was searched in both declared VCEP full-text files using c.23C>G, p.Thr8Arg, and p.T8R; no exact entry was found.

6

Only PM3 and BP2 were adjudicated. The MSH2-specific VCEP specification governs both criteria.

7

PM3 cannot be assigned without documented affected-proband co-occurrence, a second pathogenic/likely pathogenic MSH2 variant, and phase or CMMRD clinical evidence; BP2 is explicitly not applicable.

8

Population evidence supports PM2 at Supporting strength under the governing MSH2 VCEP; BA1 and BS1 are not met because the gnomAD v4.1 Grpmax FAF is below both benign-frequency thresholds.

9

BS2 remains not assessed because the VCEP requires patient-level confirmed in-trans co-occurrence and clinical context not supplied by the population dataset.

Final determination: Rule31 in the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MSH2 Version 2.0 v2.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Uncertain Significance - Conflicting Evidence.

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	N/A	Not applicable: c.23C>G produces missense p.(Thr8Arg), not an MSH2 loss-of-function variant eligible for the VCEP PVS1 rule.	cspec
PS1	Not assessed	Not assessed: no VCEP-established pathogenic alternative nucleotide encoding p.Thr8Arg was identified in the reviewed evidence.	cspec pm5_candidates
PS2	Not assessed	Not assessed: no documented proband, parental confirmation, de novo observation, Lynch-spectrum tumor, or de novo point total is available for applying the MSH2 PS2 thresholds.	cspec
PS3	Not assessed	Not assessed: the calibrated assay defines abnormal MSH2 function as LOF score >0.4, but no variant-specific LOF score is reported for p.(Thr8Arg).	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart PMID:33357406
PS4	N/A	Not applicable: the MSH2 InSiGHT VCEP explicitly excludes PS4 proband-counting evidence for MMR variant classification.	cspec
PM1	N/A	Not applicable: the MSH2 VCEP marks PM1 Not Applicable, and its authoritative domain_tables list is empty.	cspec vcep_mmr_functional_domains
PM2	Met	Met at Supporting: gnomAD v4.1 Grpmax FAF is 4.43e-06, below the MSH2 VCEP PM2 threshold of 0.00002.	cspec gnomad_v4 vcep_vcep_pilot_variants_mmr
PM3	Not assessed	Not assessed: no affected-proband co-occurrence, second pathogenic MSH2 variant, phase result, or CMMRD feature assessment is documented for PM3 point assignment.	cspec
PM4	N/A	Not applicable: the MSH2 VCEP explicitly designates PM4 as Not Applicable, and p.(Thr8Arg) causes no protein-length change.	cspec
PM5	Not met	Not met: no same-residue comparator was found, and HCI prior 0.0013 is below the VCEP PP3 supporting threshold of >0.68.	cspec pm5_candidates hci_prior vcep_hci_priors_msh2
PM6	N/A	Not applicable: the governing InSiGHT MSH2 specification designates PM6 as not applicable and routes assumed de novo evidence through PS2.	cspec
PP1	Not assessed	Not assessed: no pedigree data or combined segregation Bayes likelihood ratio is documented, leaving the PP1 Supporting threshold of >2.08 unevaluable.	cspec
PP2	N/A	Not applicable: the governing MSH2 VCEP explicitly marks PP2 as Not Applicable.	cspec
PP3	Not met	Not met: HCI pathogenicity probability 0.0013 is below the MSH2 VCEP PP3 Supporting threshold of >0.68, and REVEL 0.516 is below 0.644.	cspec vcep_hci_priors_msh2 revel bayesdel
PP4	Not assessed	Not assessed: no patient-specific MSI, IHC, tumor-genome, or CMMRD score is available to meet the VCEP PP4 thresholds.	cspec vcep_table_for_cmmrd_diagnosis vcep_vcep_pilot_variants_mmr
PP5	N/A	Not applicable: PP5 is excluded by the VCEP and ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic classification.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 Grpmax FAF is 4.43e-06, below the MSH2 VCEP BA1 threshold of 0.001.	cspec gnomad_v4 vcep_vcep_pilot_variants_mmr
BS1	Not met	Not met: gnomAD v4.1 Grpmax FAF is 4.43e-06, below the MSH2 VCEP BS1 lower threshold of 0.0001.	cspec gnomad_v4 vcep_vcep_pilot_variants_mmr
BS2	Not assessed	Not assessed: gnomAD v4.1 has zero homozygotes, but VCEP BS2 requires confirmed in-trans patient co-occurrence and clinical-age evidence.	cspec gnomad_v4 vcep_vcep_pilot_variants_mmr
BS3	Not assessed	Not assessed: the calibrated assay defines normal MSH2 function as LOF score <=0, but no variant-specific LOF score is reported for p.(Thr8Arg).	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart PMID:33357406
BS4	Not assessed	Not assessed: no documented non-segregating relatives or combined segregation Bayes likelihood ratio is available to evaluate the BS4 Strong cutoff of <0.05.	cspec
BP1	N/A	Not applicable: the governing MSH2 VCEP explicitly marks BP1 as Not Applicable.	cspec
BP2	N/A	Not applicable: the InSiGHT MSH2 Version 2.0 specification explicitly designates BP2 as not applicable.	cspec
BP3	N/A	Not applicable: the MSH2 VCEP explicitly designates BP3 as Not Applicable, and p.(Thr8Arg) is not an in-frame repeat-region indel.	cspec
BP4	Met	Met, supporting: HCI pathogenicity probability 0.0013 is below the MSH2 VCEP BP4 threshold of <0.11.	cspec vcep_hci_priors_msh2 revel bayesdel
BP5	Not assessed	Not assessed: no qualifying MSS, MMR-IHC discordant, BRAF V600E, or MLH1-methylation tumor evidence is documented.	cspec
BP6	N/A	Not applicable: BP6 is excluded by the VCEP and no exact-variant expert-panel Benign or Likely benign classification exists.	cspec clinvar
BP7	N/A	Not applicable: c.23C>G is a missense variant producing p.Thr8Arg, not a synonymous or qualifying intronic variant.

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