Variant classification summary

NM_000179.3:c.1474A>G

MSH6 · NP_000170.1:p.(Met492Val) · NM_000179.3

GRCh37: chr2:48026596 A>G · GRCh38: chr2:47799457 A>G

Gene: MSH6 Transcript: NM_000179.3

Final call

VUS

BP4 supporting

Variant details

Gene

MSH6

Transcript

NM_000179.3

Protein

NP_000170.1:p.(Met492Val)

gnomAD AF

0.00010160800869368036 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP4 supporting: the VCEP HCI prior probability is 0.0086, below the <0.11 threshold.

Final determination: Under the ClinGen InSiGHT MSH6 Version 2.0 criteria-combination framework, one supporting benign criterion alone matches no benign, likely benign, likely pathogenic, or pathogenic rule, resulting in 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: c.1474A>G is a missense variant producing p.Met492Val, not an MSH6 nonsense, frameshift, canonical splice, deletion, or duplication variant covered by PVS1.	cspec vcep_pvs1_decisiontree_mmr pvs1_variant_assessment PMID:22495361
PS1	Not met	Not met: no qualifying alternate nucleotide change encoding the same p.Met492Val substitution was established as Pathogenic by the MSH6 VCEP.	cspec PMID:12658575 PMID:18566915 PMID:22102614 PMID:22495361
PS2	Not assessed	Not assessed: no documented de novo status, confirmed maternity and paternity, or qualifying MMR-deficient tumor is available for the proband.	cspec
PS3	Not met	Not met: cell-free mismatch-repair testing found p.Met492Val repair proficient, with no calibrated pathogenicity odds supporting PS3.	cspec PMID:22102614
PS4	N/A	Not applicable: the MSH6 Version 2.0 specification explicitly designates PS4 as not applicable.	cspec
PM1	N/A	Not applicable: the governing MSH6 VCEP explicitly designates PM1 as not applicable, despite p.Met492Val being described in an MSH2-binding site.	cspec PMID:22495361 vcep_mmr_functional_domains
PM2	Not met	Not met: gnomAD v4.1 total allele frequency is 0.000101608, exceeding the MSH6 PM2 threshold of 0.00002.	cspec gnomad_v4
PM3	Not assessed	Not assessed: no pathogenic second MSH6 variant, CMMRD phenotype, or parent/offspring-confirmed phase is documented for the reported p.Met492Val observations.	cspec PMID:12658575 PMID:18566915 PMID:22495361
PM4	N/A	Not applicable: p.Met492Val is a missense substitution with no in-frame insertion, deletion, or protein-length change eligible for PM4.	cspec pvs1_variant_assessment
PM5	Not assessed	Not assessed: no qualifying alternate missense comparator at MSH6 residue 492 was available, and the required comparator search ended with a retrieval failure.	cspec PMID:22102614 PMID:22495361
PM6	N/A	Not applicable: the MSH6 InSiGHT Version 2.0 specification explicitly excludes PM6.	cspec
PP1	Not assessed	Not assessed: p.Met492Val was reported in families, but no pedigree counts, meioses, or Bayes likelihood ratio are provided for segregation.	cspec PMID:12658575 PMID:18566915 PMID:22495361
PP2	N/A	Not applicable: the governing MSH6 VCEP explicitly designates PP2 as not applicable for this gene.	cspec
PP3	Not met	Not met: the governing HCI prior probability is 0.0086, below the PP3 supporting threshold of >0.68.	cspec vcep_hci_priors_msh6
PP4	Not assessed	Not assessed: reported tumors lacked qualifying MSH6-consistent findings, while the available records do not establish a qualifying MSI-H tumor or protein-loss result.	cspec PMID:22495361 PMID:12658575
PP5	N/A	Not applicable: the MSH6 specification excludes PP5, and ClinVar shows zero exact-variant expert-panel submissions.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax filtering allele frequency is 0.00008673, below the MSH6 BA1 threshold of 0.0022.	cspec gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 grpmax filtering allele frequency is 0.00008673, below the MSH6 BS1 lower threshold of 0.00022.	cspec gnomad_v4
BS2	Not assessed	Not assessed: no documented qualifying in-trans pathogenic variant, cancer-age criterion, CMMRD assessment, and confirmed phase are available for MSH6 BS2.	cspec
BS3	Not assessed	Not assessed: p.Met492Val was repair proficient in one assay, but calibrated odds and the VCEP-required concordant protein-plus-mRNA evidence are unavailable.	cspec PMID:22102614
BS4	Not assessed	Not assessed: no affected non-carriers, pedigree-level non-segregation analysis, or Bayes likelihood ratio is reported.	cspec PMID:12658575 PMID:18566915 PMID:22495361
BP1	N/A	Not applicable: the governing MSH6 VCEP explicitly designates BP1 as not applicable for this gene.	cspec
BP2	N/A	Not applicable: the MSH6 VCEP excludes BP2 and explicitly directs this evidence to BS2 instead.	cspec
BP3	N/A	Not applicable: the MSH6 VCEP designates BP3 as not applicable, and p.Met492Val is not an in-frame deletion in a repetitive region.	cspec pvs1_variant_assessment
BP4	Met	Met, Supporting: the governing HCI prior probability is 0.0086, below the BP4 threshold of <0.11.	cspec vcep_hci_priors_msh6
BP5	Not assessed	Not assessed: no qualifying set of at least 2 exact-variant-associated tumors meeting the MSH6 BP5 benign-pattern rule is documented.	cspec PMID:22495361 PMID:12658575
BP6	N/A	Not applicable: the MSH6 specification excludes BP6, and no exact-variant ClinVar expert-panel benign assertion exists.	cspec clinvar
BP7	N/A	Not applicable: c.1474A>G is a missense variant producing p.Met492Val, not a synonymous or qualifying intronic variant.	cspec

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