NM_000251.3:c.182A>C

MSH2 · NP_000242.1:p.(Gln61Pro) · NM_000251.3

GRCh37: chr2:47630512 A>C · GRCh38: chr2:47403373 A>C

Gene: MSH2 Transcript: NM_000251.3

Final call

VUS

PM2 supporting

Variant details

Gene

MSH2

Transcript

NM_000251.3

Protein

NP_000242.1:p.(Gln61Pro)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The MSH2 c.182A>C (p.Gln61Pro) variant has not been observed in COSMIC and has been reported in ClinVar with conflicting interpretations, including uncertain significance and likely benign submissions.

This variant is present at extremely low frequency in gnomAD v4.1 (5/1,606,956 alleles; AF 3.11e-06; grpmax FAF 1.24e-06), which is below the InSiGHT MSH2 PM2_Supporting threshold of 0.00002.

Published MSH2 functional studies are cited for this variant class, but no verified variant-specific assay result or calibrated functional evidence was identified for p.(Gln61Pro), so PS3 and BS3 are not supported at this time.

In silico data show no meaningful predicted splice effect by SpliceAI (max delta 0.01), while missense predictors show a damage signal (REVEL 0.72; BayesDel 0.0679979); however, the MSH2 PP3/BP4 framework is based on HCI prior probabilities, which were not identified here.

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
PP4	Not assessed	No tumor MSI, immunohistochemistry, or phenotype data were identified to determine whether this variant is associated with Lynch syndrome features meeting the MSH2-specific PP4 thresholds.	cspec
BP3	N/A	BP3 is not applicable in this MSH2 framework.	cspec
BP7	N/A	This is a missense variant, not a synonymous or qualifying intronic change, so BP7 does not apply.	cspec spliceai
BS4	Not assessed	No family-based non-segregation data or Bayes likelihood ratio were identified for this variant, so BS4 cannot be assessed.	cspec
BS3	Not assessed	Published MSH2 functional studies are cited for this variant class, but no verified variant-specific calibrated assay result or proficient function result for p.(Gln61Pro) was identified to support BS3.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart PMID:17720936 PMID:20176959 PMID:33357406
PM5	Not assessed	No MSH2 expert-panel Pathogenic or Likely Pathogenic missense variant at residue Gln61 was identified in the available materials, so PM5 cannot be assigned.	cspec vcep_vcep_pilot_variants_mmr
BP2	N/A	BP2 is not applicable in this MSH2 framework.	cspec
PM2	Met	This variant is present at extremely low frequency in gnomAD v4.1 (5/1,606,956 alleles; AF 3.11e-06; highest population AF 4.25e-06 in European non-Finnish; grpmax FAF 1.24e-06), which is below the MSH2 PM2 threshold of 0.00002 (<1 in 50,000 alleles). This supports PM2_Supporting.	cspec gnomad_v4
BP4	Not assessed	For missense variants in this MSH2 framework, BP4 requires an HCI prior probability of pathogenicity below 0.11, and that value was not identified. SpliceAI predicts no meaningful splice impact (max delta 0.01), but that intronic/synonymous splicing rule does not establish BP4 for this missense change. REVEL is 0.72 and BayesDel is 0.0679979, which do not support benign computational evidence.	cspec spliceai revel bayesdel
BP6	N/A	BP6 is not applicable in this MSH2 framework.	cspec
PS1	Not assessed	No previously established Pathogenic or Likely Pathogenic variant encoding the same amino acid change was identified in the available materials, so PS1 cannot be assigned.	cspec clinvar
PS2	Not assessed	No de novo observation with confirmed parentage was identified for this variant, so PS2 cannot be assessed.	cspec clinvar
BS1	Not met	The gnomAD v4.1 frequency is far below the BS1 threshold. The highest observed population frequency is 4.25e-06, which is below the required threshold of at least 0.0001 and therefore does not support BS1.	cspec gnomad_v4
PM1	N/A	PM1 is not applicable in this MSH2 framework.	cspec vcep_mmr_functional_domains
PP5	N/A	PP5 is not applicable in this MSH2 framework.	cspec
PP1	Not assessed	No co-segregation data or Bayes likelihood ratio were identified for this variant, so PP1 cannot be assessed.	cspec
BP5	Not assessed	No tumor evidence was identified showing microsatellite-stable disease, retained MMR protein expression, or MMR protein loss inconsistent with MSH2, so BP5 cannot be assessed.	cspec
PM6	N/A	PM6 is not applicable in this MSH2 framework.	cspec
BA1	Not met	The gnomAD v4.1 frequency is well below the BA1 threshold. The highest observed population frequency is 4.25e-06, which is below 0.001 and therefore does not support BA1.	cspec gnomad_v4
PVS1	N/A	This variant is a missense substitution, NM_000251.3:c.182A>C (p.Gln61Pro), and it does not fall into the MSH2 PVS1 null-variant categories of nonsense, frameshift, canonical +/-1 or 2 splice, or proven null splicing defect. SpliceAI predicts no significant splice impact (max delta score 0.01), so available evidence does not support a loss-of-function mechanism for PVS1.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS4	N/A	PS4 is not applicable in this MSH2 framework.	cspec clinvar
PM4	N/A	PM4 is not applicable in this MSH2 framework.	cspec
PS3	Not assessed	Published MSH2 functional studies are cited for this variant class, but no verified variant-specific calibrated assay result, OddsPath value, or flowchart-supported mismatch repair defect for p.(Gln61Pro) was identified to support PS3.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart PMID:17720936 PMID:20176959 PMID:33357406
PP3	Not assessed	For missense variants in this MSH2 framework, PP3 requires an HCI prior probability above 0.68 or 0.81 depending on strength, and that value was not identified. REVEL is 0.72 and BayesDel is 0.0679979, which are consistent with a missense-damage signal, but the official MSH2 PP3 rule is HCI-based. SpliceAI predicts no meaningful splice impact (max delta 0.01), so there is no computational support for a splice mechanism.	cspec revel bayesdel spliceai
BS2	Not assessed	No confirmed in trans co-occurrence with a known pathogenic MSH2 variant and no accompanying age or CMMRD-exclusion data were identified, so BS2 cannot be assessed.	cspec vcep_table_for_cmmrd_diagnosis
BP1	N/A	BP1 is not applicable in this MSH2 framework.	cspec
PM3	Not assessed	No biallelic case data or phase-confirmed observations were identified for this variant, so PM3 cannot be assessed.	cspec
PP2	N/A	PP2 is not applicable in this MSH2 framework.	cspec

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