Variant classification summary

NM_000179.3:c.242C>T

MSH6 · NP_000170.1:p.(Ala81Val) · NM_000179.3

GRCh37: chr2:48010614 C>T · GRCh38: chr2:47783475 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.(Ala81Val)

gnomAD AF

0.00011394364514058145 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: BP4 Supporting - the exact MSH6 HCI prior is 0.0035, below the VCEP missense threshold of <0.11.

Final determination: Under the ClinGen InSiGHT MSH6 Version 2.0 criteria-combination framework, BP4 Supporting alone does not satisfy any pathogenic, likely pathogenic, likely benign, or benign rule, so the result is 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	Not met	Not met: NM_000179.3:c.242C>T is a missense variant producing p.(Ala81Val), outside the MSH6 VCEP PVS1 null-variant categories.	cspec pvs1_variant_assessment
PS1	Not met	Not met: no documented VCEP-Pathogenic alternate nucleotide change producing the same p.Ala81Val substitution was identified.	cspec clinvar
PS2	Not assessed	Not assessed: no documented de novo observation with maternity and paternity confirmation or variant-specific tumor evidence is available for this variant.	cspec
PS3	Not assessed	Not assessed: no variant-specific functional assay result or calibrated pathogenicity odds are available for MSH6 c.242C>T.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart PMID:26467025 PMID:27363726
PS4	N/A	Not applicable: the MSH6 VCEP specification explicitly excludes PS4 from MMR variant classification using proband counting.	cspec
PM1	N/A	Not applicable: the MSH6 VCEP explicitly marks PM1 Not Applicable, and no approved domain-table entry is present for residue 81.	cspec vcep_mmr_functional_domains
PM2	Not met	Not met: gnomAD v4.1 total AF is 0.000113943645, exceeding the MSH6 PM2 threshold of <0.00002.	cspec gnomad_v4
PM3	Not assessed	Not assessed: no qualifying affected-proband biallelic observation or documented cis/trans phase was available to assign the MSH6 PM3 point thresholds.	cspec
PM4	N/A	Not applicable: the MSH6 VCEP explicitly excludes PM4, and this variant causes a missense substitution without a protein-length change.	cspec
PM5	Not assessed	Not assessed: 0 same-residue candidates were available, but comparator harvesting ended with an HTTP 429 failure, leaving PM5 evidence incomplete.	cspec pm5_candidates
PM6	N/A	Not applicable: the MSH6 InSiGHT VCEP Version 2.0 explicitly designates PM6 as not applicable.	cspec
PP1	Not assessed	Not assessed: no pedigree segregation data or combined Bayes likelihood ratio is reported, so the VCEP thresholds >2.08, >4.3, and >18.7 cannot be evaluated.	cspec
PP2	N/A	Not applicable: the governing MSH6 VCEP explicitly marks PP2 Not Applicable.	cspec
PP3	Not met	Not met: HCI prior 0.0035 is below the MSH6 VCEP PP3 threshold of >0.68, and REVEL 0.216 is below the generic 0.644 threshold.	vcep_hci_priors_msh6 cspec revel bayesdel
PP4	Not assessed	Not assessed: exact-variant cancer observations lack the required MSI-H, tumor-genome, or MSH6-consistent IHC findings and qualifying tumor count.	cspec clinvar
PP5	N/A	Not applicable: the MSH6 VCEP excludes PP5, and ClinVar has zero exact-variant expert-panel submissions.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.00012624, below the MSH6 BA1 threshold of 0.0022.	cspec gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.00012624, below the MSH6 BS1 lower boundary of 0.00022.	cspec gnomad_v4
BS2	Not assessed	Not assessed: no documented MSH6 pathogenic-variant co-occurrence in trans with qualifying cancer age, CMMRD assessment, and confirmed phase.	cspec gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific proficient-function assay result or calibrated benign functional odds are available for MSH6 c.242C>T.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart PMID:26467025 PMID:27363726
BS4	Not assessed	Not assessed: no non-segregation observations or combined Bayes likelihood ratio is reported, so the BS4 thresholds <0.05 and 0.05-0.48 cannot be evaluated.	cspec
BP1	N/A	Not applicable: the governing MSH6 VCEP explicitly marks BP1 Not Applicable.	cspec
BP2	N/A	Not applicable: the MSH6 Version 2.0 VCEP explicitly excludes BP2, so no co-occurrence threshold is applied.	cspec
BP3	N/A	Not applicable: the MSH6 VCEP explicitly excludes BP3, and this missense variant does not create an in-frame repeat-region deletion.	cspec
BP4	Met	Met, supporting: exact HCI prior 0.0035 is below the MSH6 VCEP BP4 threshold of <0.11 for missense variants.	vcep_hci_priors_msh6 cspec revel spliceai
BP5	Not assessed	Not assessed: no variant-specific MSS, MMR-IHC inconsistency, BRAF V600E, MLH1 methylation, or qualifying tumor count is documented.	cspec clinvar
BP6	N/A	Not applicable: the MSH6 VCEP excludes BP6, and ClinVar has no exact-variant expert-panel benign assertion.	cspec clinvar
BP7	N/A	Not applicable: c.242C>T changes Ala81 to Val and is missense, whereas BP7 is limited to synonymous or qualifying intronic variants.	cspec

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