Variant classification summary

NM_000251.3:c.1847C>G

MSH2 · NP_000242.1:p.(Pro616Arg) · NM_000251.3

GRCh37: chr2:47702251 C>G · GRCh38: chr2:47475112 C>G

Gene: MSH2 Transcript: NM_000251.3

Final call

VUS

PP3 moderate BS1 strong

Variant details

Gene

MSH2

Transcript

NM_000251.3

Protein

NP_000242.1:p.(Pro616Arg)

gnomAD AF

3.221885025793668e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: PP3 moderate because the MSH2 HCI prior probability for p.Pro616Arg is 0.900, above the >0.81 moderate cutoff.

2

VUS: BS1 strong because the gnomAD v4.1 Grpmax FAF of 0.00018 falls inside the framework's 0.0001-0.001 benign-frequency window.

3

VUS: BS1 (strong benign) together with PP3 (moderate pathogenic) matches the MSH2 v2.0 Rule22 conflicting-evidence combination.

Final determination: Under the ClinGen InSiGHT MSH2 v2.0 criteria-combination rules, at least one Benign Strong criterion (BS1) combined with at least one Pathogenic Moderate criterion (PP3) satisfies Rule22 and yields Uncertain Significance - Conflicting Evidence, i.e. VUS.

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	Not met	Not met: c.1847C>G is a missense substitution (p.Pro616Arg) with no PTC, frameshift or protein-length change and SpliceAI max delta 0.001.	cspec spliceai vcep_pvs1_decisiontree_mmr vcep_vcep_pilot_variants_mmr
PS1	Not met	Not met: codon 616 is CCT and only c.1847C>G encodes p.Pro616Arg, so no alternate nucleotide change exists for the PS1 comparator.	cspec vcep_hci_priors_msh2 vcep_vcep_pilot_variants_mmr clinvar PMID:25741868
PS2	Not assessed	Not assessed: no proband, parental confirmation, or Lynch-spectrum tumour data exists to award any MSH2 de novo points (0.5 points minimum).	cspec
PS3	Not assessed	Not assessed: the approved calibrated MSH2 assay defines abnormal function as LoF score >0.4, but no variant-specific score is reported for p.(Pro616Arg).	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart vcep_hci_priors_msh2 PMID:33357406 PMID:32849802 PMID:25741868 oncokb
PS4	N/A	Not applicable: the InSiGHT MSH2 v2.0 specification designates PS4 'Not Applicable', and no case-control enrichment statistic exists for c.1847C>G.	cspec clinvar
PM1	N/A	Not applicable: the MSH2 v2.0 specification disables PM1 at every strength, stating there are no recognized mutational hotspots and pathogenic variants are distributed across all MMR domains.	cspec vcep_mmr_functional_domains PMID:25741868 PMID:33357406
PM2	Not met	Not met: gnomAD v4.1 all-allele frequency 3.22e-05 exceeds the InSiGHT MSH2 v2.0 PM2 cutoff of <0.00002.	cspec gnomad_v4 gnomad_v2 vcep_vcep_pilot_variants_mmr
PM3	Not met	Not met: no co-occurrence with a pathogenic/likely pathogenic MSH2 variant in a CMMRD-featured patient, scoring 0 points versus the 0.5-point Supporting threshold.	cspec vcep_table_for_cmmrd_diagnosis clinvar gnomad_v4 gnomad_v2
PM4	N/A	Not applicable: MSH2 VCEP v2.0 marks PM4 not applicable, and this missense substitution (p.Pro616Arg) causes no protein-length change.	cspec
PM5	Not met	Not met: all five alternative codon-616 substitutions in ClinVar are Uncertain significance, Likely benign or conflicting, and none is classified Pathogenic or Likely Pathogenic by the VCEP.	cspec clinvar pm5_candidates vcep_vcep_pilot_variants_mmr vcep_hci_priors_msh2 PMID:25741868
PM6	N/A	Not applicable: the governing InSiGHT MSH2 v2.0 specification marks PM6 not applicable and routes assumed de novo evidence to PS2 at 0.5 points.	cspec
PP1	Not assessed	Not assessed: no pedigree or segregation Bayes likelihood ratio exists to compare with the PP1 Supporting threshold of >2.08.	cspec
PP2	N/A	Not applicable: the MSH2 v2.0 specification disables PP2, stating the criterion for a gene with a low rate of benign missense changes does not apply.	cspec vcep_hci_priors_msh2 PMID:25741868
PP3	Met	Met at Moderate: the VCEP HCI prior probability for c.1847C>G (p.P616R) is 0.900, above the >0.81 PP3_Moderate cutoff.	cspec hci_prior vcep_hci_priors_msh2 revel
PP4	Not met	Not met: 0 documented MSI-H tumors with concordant MMR protein loss against the minimum PP4_Supporting requirement of 1 (0 >= 1 is false).	cspec clinvar vcep_table_for_cmmrd_diagnosis vcep_vcep_pilot_variants_mmr PMID:28135145
PP5	N/A	Not applicable: the InSiGHT MSH2 v2.0 specification marks PP5 'Not Applicable', and ClinVar has 0 expert-panel submissions (maximum 1-star review status) for this variant.	cspec clinvar vcep_vcep_pilot_variants_mmr
BA1	Not met	Not met: gnomAD v4.1 Grpmax FAF 0.00018 is ~5.6-fold below the InSiGHT MSH2 v2.0 BA1 stand-alone cutoff of 0.001.	cspec gnomad_v4
BS1	Met	Met at Strong: gnomAD v4.1 Grpmax FAF 0.00018 falls inside the InSiGHT MSH2 v2.0 BS1 window of 0.0001-0.001.	cspec gnomad_v4 gnomad_v2 vcep_vcep_pilot_variants_mmr
BS2	Not assessed	Not assessed: no parental or offspring phase testing showing in-trans co-occurrence with a pathogenic MSH2 variant, which is what MSH2 v2.0 BS2 requires.	cspec gnomad_v4 vcep_vcep_pilot_variants_mmr vcep_table_for_cmmrd_diagnosis
BS3	Not assessed	Not assessed: the calibrated MSH2 assay defines normal function as LoF score <=0, but no variant-specific score is reported for p.(Pro616Arg).	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart vcep_hci_priors_msh2 PMID:33357406 PMID:32849802 PMID:25741868 oncokb
BS4	Not assessed	Not assessed: no non-segregating relatives or Bayes likelihood ratio exists to compare with the BS4 Strong cutoff of <0.05.	cspec
BP1	N/A	Not applicable: the MSH2 v2.0 specification disables BP1, and MSH2 missense variants are an established pathogenic mechanism, not only truncating variants.	cspec PMID:33357406 PMID:25741868
BP2	N/A	Not applicable: the InSiGHT MSH2 VCEP specification v2.0 marks BP2 Not Applicable, so no in-trans or in-cis co-occurrence is scored under this criterion.	cspec final_classification_framework PMID:25741868 clinvar
BP3	N/A	Not applicable: MSH2 VCEP v2.0 marks BP3 not applicable, and this variant is a missense substitution, not an in-frame indel in a repeat region.	cspec
BP4	Not met	Not met: the VCEP HCI prior for p.P616R is 0.900, far above the <0.11 BP4_Supporting threshold for MSH2 missense variants.	cspec hci_prior vcep_hci_priors_msh2 revel
BP5	Not met	Not met: 0 qualifying MSS/no-MMR-loss tumors documented against BP5_Supporting's minimum of 2 (2 <= 0 is false) and 0 >= 4 required for BP5_Strong.	cspec clinvar vcep_table_for_cmmrd_diagnosis vcep_vcep_pilot_variants_mmr
BP6	N/A	Not applicable: the InSiGHT MSH2 v2.0 specification marks BP6 'Not Applicable', and no exact-variant expert-panel Benign/Likely benign ClinVar assertion exists.	cspec clinvar
BP7	N/A	Not applicable: c.1847C>G (p.Pro616Arg) is a missense variant, whereas BP7 applies only to synonymous or deep-intronic variants.	cspec spliceai

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