Variant classification summary

NM_000179.2:c.2975A>G

MSH6 · NP_000170.1:p.(Glu992Gly) · NM_000179.2

GRCh37: chr2:48028097 A>G · GRCh38: chr2:47800958 A>G

Gene: MSH6 Transcript: NM_000179.2

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

MSH6

Transcript

NM_000179.2

Protein

NP_000170.1:p.(Glu992Gly)

gnomAD AF

1.9144398540431057e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): gnomAD v4.1 total allele frequency 1.91e-06 (3/1,567,038 alleles), below the VCEP 0.00002 threshold.

2

BP4 (Supporting): HCI-prior pathogenicity probability 0.0276, below the VCEP 0.11 threshold.

3

Overall: VUS — one supporting pathogenic-direction and one supporting benign-direction criterion meet VCEP Rule31 (conflicting evidence), mapped to VUS.

Final determination: Rule31 of the ClinGen InSiGHT MSH6 VCEP v2.0 criteria-combination framework (>=1 Benign.Supporting AND >=1 Pathogenic.Supporting, with no higher-strength criteria met) is satisfied by PM2 supporting and BP4 supporting, yielding Uncertain Significance - Conflicting Evidence (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: this is a missense substitution, not one of the null-variant classes (nonsense/frameshift, splice, deletion, initiation codon) covered by the VCEP rule.	cspec pvs1_variant_assessment
PS1	Not assessed	Insufficient evidence was available to confirm or exclude an alternate codon producing p.Glu992Gly that was previously classified pathogenic.	cspec pm5_candidates clinvar
PS2	Not assessed	Insufficient evidence: no documented de novo occurrence with proband status, parental testing, or confirmed maternity and paternity.	cspec
PS3	Not assessed	Insufficient evidence: no variant-specific functional assay, RNA, or monoallelic-expression data; two ClinVar submissions report no published functional studies.
PS4	N/A	Not applicable: the MSH6 VCEP specification explicitly designates PS4 as not applicable.	cspec
PM1	N/A	Not applicable: the MSH6 VCEP defines no mutational hotspot rule for this gene, superseding generic PM1.	cspec
PM2	Met	Met (Supporting): gnomAD v4.1 total allele frequency 1.91e-06 (3/1,567,038 alleles), below the VCEP 0.00002 threshold.	cspec gnomad_v4
PM3	Not assessed	Insufficient evidence: no second pathogenic MSH6 variant or documented phase from family testing to assess co-occurrence.	cspec
PM4	N/A	Not applicable: VCEP designates PM4 not applicable, and this missense causes no protein-length change.	cspec
PM5	Not met	Not met: no same-residue (codon 992) pathogenic comparator was identified, and PP3 is not met for p.Glu992Gly.	cspec pm5_candidates hci_prior
PM6	N/A	Not applicable: PM6 is explicitly designated not applicable in the MSH6 VCEP framework.	cspec
PP1	Not assessed	Insufficient evidence: no segregation data, pedigree, or informative meioses from affected family members.	cspec
PP2	N/A	Not applicable: the MSH6 VCEP explicitly marks PP2 as not applicable, superseding generic missense-constraint PP2.	cspec
PP3	Not met	Not met: HCI-prior pathogenicity probability 0.0276, below the PP3 supporting threshold of >0.68.	cspec hci_prior
PP4	Not assessed	Insufficient evidence: no patient-specific MSI-H tumor or MMR immunohistochemistry result consistent with the variant's location.	cspec
PP5	N/A	Not applicable: the MSH6 VCEP designates PP5 not applicable, and no expert-panel ClinVar submission exists for this variant.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 allele frequency 1.91e-06, far below the BA1 threshold of at least 0.0022.	cspec gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 allele frequency 1.91e-06, below the BS1 strong threshold of at least 0.00022.	cspec gnomad_v4
BS2	Not assessed	Insufficient evidence: no individual-level data on in-trans co-occurrence with a pathogenic variant, cancer age, or phase confirmation.	cspec gnomad_v4
BS3	Not assessed	Insufficient evidence: no variant-specific functional assay data (calibrated odds or proficient-function assay results).
BS4	Not assessed	Insufficient evidence: no non-segregation observations, pedigree, or Bayes likelihood ratio available.	cspec
BP1	N/A	Not applicable: the MSH6 VCEP explicitly marks BP1 as not applicable.	cspec
BP2	N/A	Not applicable: the MSH6 VCEP designates BP2 not applicable, with BS2 used instead.	cspec
BP3	N/A	Not applicable: VCEP designates BP3 not applicable, and this missense is not an in-frame indel in a repeat region.	cspec
BP4	Met	Met (Supporting): HCI-prior pathogenicity probability 0.0276, below the VCEP BP4 supporting threshold of <0.11.	cspec hci_prior
BP5	Not assessed	Insufficient evidence: no patient-specific tumor results (MSS, MMR loss patterns, or BRAF V600E/MLH1 methylation).	cspec
BP6	N/A	Not applicable: the MSH6 VCEP designates BP6 not applicable, and no expert-panel benign ClinVar assertion exists.	cspec clinvar
BP7	N/A	Not applicable: BP7 covers only synonymous or deep intronic variants; this is a missense substitution.	cspec

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