Variant classification summary

NM_000179.3:c.3787C>T

MSH6 · NP_000170.1:p.(Arg1263Cys) · NM_000179.3

GRCh37: chr2:48033483 C>T · GRCh38: chr2:47806344 C>T

Gene: MSH6 Transcript: NM_000179.3

Final call

VUS

BP4 supporting

Variant details

Gene

MSH6

Transcript

NM_000179.3

Protein

NP_000170.1:p.(Arg1263Cys)

gnomAD AF

2.3545011245840897e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP4 supporting: MSH6 HCI prior 0.0236 is below the VCEP threshold of <0.11.

2

VUS: no pathogenic or benign combination rule was satisfied by the adjudicated criteria.

Final determination: Under the ClinGen InSiGHT MSH6 Version 2.0 criteria-combination framework, BP4 supporting alone does not satisfy any pathogenic or benign rule, so the variant remains 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	N/A	Not applicable: NM_000179.3:c.3787C>T is a missense p.Arg1263Cys change, not a VCEP-defined nonsense, frameshift, qualifying splice, or truncating event.	cspec
PS1	Not met	Not met: no alternate-nucleotide p.Arg1263Cys comparator is established as Pathogenic by the MSH6 VCEP.	cspec PMID:25583476
PS2	Not assessed	Not assessed: no proband-level de novo observation, parental confirmation, or qualifying Lynch syndrome-spectrum tumor evidence is documented for this variant.	cspec
PS3	Not assessed	Not assessed: no variant-specific calibrated functional odds, MMR function-defect assay, or monoallelic-expression result is available for p.Arg1263Cys.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart
PS4	N/A	Not applicable: the governing MSH6 specification explicitly excludes PS4 and directs tumor phenotype evidence to PP4.	cspec
PM1	N/A	Not applicable: the governing MSH6 VCEP explicitly designates PM1 as Not Applicable.	cspec vcep_mmr_functional_domains
PM2	Not met	Not met: gnomAD v4.1 total AF is 2.3545e-05, above the VCEP PM2 threshold of 0.00002 despite grpmax FAF 1.994e-05.	cspec gnomad_v4
PM3	Not assessed	Not assessed: no documented CMMRD proband, second pathogenic MSH6 variant, or phase evidence is available to assign the VCEP's PM3 points.	cspec
PM4	N/A	Not applicable: the MSH6 VCEP Version 2.0 explicitly excludes PM4, and this variant is a missense substitution without a protein-length change.	cspec
PM5	Not met	Not met: zero same-residue Arg1263 comparator candidates were found, and HCI prior 0.0236 is below the PP3 Supporting threshold of >0.68.	cspec hci_prior pm5_candidates
PM6	N/A	Not applicable: the governing MSH6 VCEP explicitly designates PM6 as not applicable.	cspec
PP1	Not assessed	Not assessed: no pedigree genotypes, meioses, or combined Bayes likelihood ratio are documented to compare with the PP1 supporting threshold of >2.08.	cspec
PP2	N/A	Not applicable: the governing MSH6 VCEP explicitly designates PP2 as Not Applicable.	cspec
PP3	Not met	Not met: HCI prior 0.0236 and REVEL 0.594 are below the MSH6 PP3 supporting thresholds of >0.68 and >=0.644, respectively.	cspec hci_prior revel bayesdel
PP4	Not assessed	Not assessed: no tumor MSI, tumor-genome, or MMR IHC result is documented to compare with the PP4 phenotype-specific rule.	cspec
PP5	N/A	Not applicable: the MSH6 specification excludes PP5, and ClinVar reports zero exact-variant expert-panel submissions.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 1.994e-05, below the VCEP BA1 threshold of 0.0022.	cspec gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 1.994e-05, below the VCEP BS1 lower threshold of 0.00022.	cspec gnomad_v4
BS2	Not assessed	Not assessed: no qualifying in-trans co-occurrence, cancer age, CMMRD assessment, or phase-confirmation evidence is documented.	cspec gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific calibrated functional odds or qualifying proficient protein, mRNA, or NMD-controlled RNA assay is available for p.Arg1263Cys.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart
BS4	Not assessed	Not assessed: no non-segregating pedigree data or combined Bayes likelihood ratio is documented to compare with the BS4 strong threshold of <0.05.	cspec
BP1	N/A	Not applicable: the governing MSH6 VCEP explicitly designates BP1 as Not Applicable.	cspec
BP2	N/A	Not applicable: the MSH6 InSiGHT VCEP explicitly designates BP2 as not applicable.	cspec
BP3	N/A	Not applicable: BP3 is explicitly not applicable in the MSH6 VCEP Version 2.0, and this variant is missense rather than a repeat-region in-frame indel.	cspec
BP4	Met	Met, supporting: MSH6 HCI prior 0.0236 is below the governing BP4 threshold of <0.11 for missense variants.	cspec hci_prior revel bayesdel
BP5	Not assessed	Not assessed: the required tumor count and MSS, MMR-IHC, BRAF V600E, or MLH1-methylation evidence are not documented.	cspec
BP6	N/A	Not applicable: the MSH6 specification excludes BP6, and ClinVar reports zero exact-variant expert-panel submissions.	cspec clinvar
BP7	N/A	Not applicable: c.3787C>T is a missense variant encoding p.Arg1263Cys, not a synonymous or qualifying intronic variant.	cspec

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