Variant classification summary

NM_000251.2:c.1381G>A

MSH2 · NP_000242.1:p.(Asp461Asn) · NM_000251.2

GRCh37: chr2:47672791 G>A · GRCh38: chr2:47445652 G>A

Gene: MSH2 Transcript: NM_000251.2

Final call

PM2 supporting BP4 supporting benign

Variant details

Gene

MSH2

Transcript

NM_000251.2

Protein

NP_000242.1:p.(Asp461Asn)

gnomAD AF

6.312676991681154e-07 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000251.2:c.1381G>A (p.Asp461Asn) is a missense variant in MSH2 exon 8. It is absent from ClinVar and extremely rare in gnomAD v4.1 (1/1,584,114 alleles; AF=6.31e-07), meeting PM2_Supporting under the InSiGHT MSH2 VCEP v2.0.0.

2

In silico predictions are concordantly benign: HCI prior probability is 0.0014 (<0.11 threshold), REVEL is 0.296, BayesDel is -0.07, and SpliceAI predicts no splicing impact (max delta=0.01). This meets BP4_Supporting under the VCEP framework.

3

No functional data, co-segregation data, tumor phenotype data, or de novo observations are available for this variant. No same-residue comparator variants classified as pathogenic by this VCEP were identified. PVS1, PS1, PS2, PS3, PS4, PS5, PM1, PM5, PM6, PP1, PP2, PP3, PP4, PP5, BA1, BS1, BS2, BS3, BS4, BP1, BP2, BP5, BP6, and BP7 are either not met or not applicable.

4

With one pathogenic supporting criterion (PM2_Supporting) and one benign supporting criterion (BP4_Supporting), the evidence is insufficient to classify this variant. The variant is classified as a Variant of Uncertain Significance (VUS) under the InSiGHT MSH2 VCEP v2.0.0 combining rules.

Final determination: Rule31 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 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	Missense substitution; VCEP PVS1 rules apply only to null variants (nonsense, frameshift, splice consensus, CNV) and not to missense changes.
PS1	Not met	No different nucleotide change encoding the same amino acid substitution (p.Asp461Asn) has been previously classified as Pathogenic or Likely Pathogenic by this VCEP. The variant is absent from ClinVar and no PS1 comparator exists.	clinvar vcep_vcep_pilot_variants_mmr
PS2	Not met	No de novo observations for this variant have been reported in the literature or clinical databases.
PS3	Not met	No functional assay data exists for NM_000251.2:c.1381G>A (p.Asp461Asn). OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence. The VCEP functional assay documentation spreadsheet does not list this variant among tested residues.	oncokb vcep_functional_assay_svi_documentation_mmr
PS4	N/A	VCEP marks PS4 as Not Applicable for MSH2.	cspec
PS5	Not met	No different missense change at codon 461 has been established as pathogenic. PM5 candidate search returned zero same-residue comparators in ClinVar, and the VCEP pilot variant spreadsheet contains no classifications for codon 461. No evidence supports PS5.	clinvar vcep_vcep_pilot_variants_mmr
PM1	N/A	VCEP explicitly marks PM1 as Not Applicable for MSH2.	cspec
PM2	Met	This variant is present in gnomAD v4.1 at an allele frequency of 6.31e-07 (1/1,584,114 alleles; 0 homozygotes), well below the VCEP PM2_Supporting threshold of <0.00002 (<1 in 50,000 alleles). It is absent from gnomAD v2.1.	gnomad_v2 gnomad_v4 cspec
PM5	Not met	No different missense change at codon 461 has been classified as Pathogenic or Likely Pathogenic by this VCEP. The PM5 candidate search returned zero same-residue comparator variants. VCEP PM5 additionally requires PP3 to be supporting, which is not met (HCI prior=0.0014).	clinvar vcep_vcep_pilot_variants_mmr
PM6	N/A	VCEP marks PM6 as Not Applicable for MSH2.	cspec
PP1	Not met	No co-segregation data available for this variant.
PP2	N/A	VCEP marks PP2 as Not Applicable for MSH2.	cspec
PP3	Not met	In silico predictions do not support a deleterious effect. HCI prior probability for pathogenicity is 0.0014, well below the VCEP PP3_Supporting threshold of >0.68. REVEL score is 0.296 (not strongly pathogenic), BayesDel score is -0.07 (benign direction), and SpliceAI max delta is 0.01 (no predicted splicing impact).	hci_prior revel bayesdel spliceai cspec
PP4	Not met	No tumor data (MSI status, MMR immunohistochemistry) are available to assess whether the patient's phenotype is specific for Lynch syndrome. VCEP PP4 requires MSI-H tumor data and/or loss of MMR protein expression consistent with the variant location.	cspec
PP5	N/A	VCEP marks PP5 as Not Applicable for MSH2.	cspec
BA1	Not met	gnomAD v4.1 allele frequency is 6.31e-07, far below the VCEP BA1 threshold of >=0.001 (>=0.1%). The variant is not a common polymorphism.	gnomad_v4 cspec
BS1	Not met	gnomAD v4.1 allele frequency is 6.31e-07, far below the VCEP BS1 threshold of >=0.0001 (>=0.01%).	gnomad_v4 cspec
BS2	Not met	No data on co-occurrence in trans with a known pathogenic MSH2 variant in an individual without CMMRD features.
BS3	Not met	No functional data demonstrating normal or proficient MMR function for this variant. VCEP BS3 requires calibrated functional assays with functional odds for pathogenicity <=0.05, or variant-specific proficient function in MMR assays. No such data exist for p.Asp461Asn.	oncokb vcep_functional_assay_svi_documentation_mmr
BS4	Not met	No co-segregation data available to assess lack of segregation with disease.
BP1	N/A	VCEP marks BP1 as Not Applicable for MSH2.	cspec
BP2	N/A	VCEP marks BP2 as Not Applicable for MSH2.	cspec
BP3	N/A	In-frame deletion/insertion criterion not applicable to this missense substitution.
BP4	Met	HCI prior probability for pathogenicity is 0.0014, well below the VCEP BP4_Supporting threshold of <0.11. Multiple in silico predictors concordantly suggest a benign effect: REVEL=0.296, BayesDel=-0.07, SpliceAI max delta=0.01 (no splicing impact).	hci_prior revel bayesdel spliceai cspec
BP5	Not met	No tumor data available to assess MSS status or MMR protein expression. VCEP BP5 requires observation of MSS tumors and/or retained MMR protein expression inconsistent with the gene harboring the variant.
BP6	N/A	VCEP marks BP6 as Not Applicable for MSH2.	cspec
BP7	N/A	Non-synonymous missense variant; BP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7.	cspec
PM3	N/A	Trans co-occurrence assessment not applicable in the absence of biallelic genotype data.
PM4	N/A	Protein length change criterion not applicable to this missense substitution.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.