Variant classification summary

NM_000179.3:c.1403G>A

MSH6 · NP_000170.1:p.(Arg468His) · NM_000179.3

GRCh37: chr2:48026525 G>A · GRCh38: chr2:47799386 G>A

Gene: MSH6 Transcript: NM_000179.3

Final call

Likely Benign

PM2 supporting BP4 supporting BP6 supporting benign

Variant details

Gene

MSH6

Transcript

NM_000179.3

Protein

NP_000170.1:p.(Arg468His)

gnomAD AF

1.920720108948201e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): gnomAD v4.1 total allele frequency 0.00192% is below the 0.002% (1 in 50,000) rarity threshold.

2

BP4 (Supporting): HCI prior probability of pathogenicity 0.1095 is below the 0.11 benign threshold.

3

BP6 (Supporting Benign): the InSiGHT expert panel classified this exact variant Likely Benign (ClinVar 3-star review).

4

Overall: Likely Benign, by VCEP Rule19 (two or more Benign.Supporting criteria).

Final determination: Under the InSiGHT MSH6 VCEP v2.0 combination rules, at least two benign supporting criteria (BP4 supporting + BP6 supporting benign) satisfy Rule19, classifying the variant as Likely Benign, while the single pathogenic supporting criterion (PM2 supporting) reaches no pathogenic combination.

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: c.1403G>A is a missense substitution with no protein length change and no splicing impact (SpliceAI max delta 0.02).	cspec spliceai pvs1_variant_assessment pvs1_gene_context clinvar PMID:18033691
PS1	Not met	Not met: no alternative nucleotide change producing p.Arg468His has been classified pathogenic; the only such allele, c.1403G>A itself, is InSiGHT Likely Benign.	cspec clinvar spliceai pm5_candidates PMID:18033691
PS2	Not assessed	Not assessed: no de novo occurrence or parental testing data were available for this variant.	cspec clinvar PMID:18033691
PS3	Not met	Not met: four independent laboratory assays report proficient mismatch repair activity similar to wild type, contradicting a damaging effect.	clinvar spliceai vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart PMID:18033691
PS4	N/A	Not applicable: the InSiGHT MSH6 VCEP does not use PS4; phenotype specificity is captured by PP4 and population enrichment by BS1/BA1.	cspec PMID:18033691 PMID:18809606
PM1	N/A	Not applicable: the MSH6 VCEP recognizes no mutational hotspots usable for classification in this gene.	cspec oncokb vcep_mmr_functional_domains
PM2	Met	Met (supporting): gnomAD v4.1 total allele frequency 0.00192% is below the 0.002% (<1 in 50,000) threshold. Flagged for human review: grpmax FAF and AMR subpopulation frequencies exceed the threshold, leaving essentially no margin.	gnomad_v4 gnomad_v2 PMID:18033691 cspec
PM3	Not met	Not met: no in-trans or biallelic co-occurrence with a pathogenic MSH6 variant is documented; gnomAD reports 0 homozygotes.	cspec clinvar gnomad_v4 vcep_table_for_cmmrd_diagnosis PMID:18033691 PMID:19389263 PMID:21153778
PM4	N/A	Not applicable: the MSH6 VCEP does not use protein-length-change evidence, and this missense does not alter protein length.	cspec PMID:18033691
PM5	Not met	Not met: no pathogenic missense at residue 468 exists, and the PP3 gate fails (HCI prior 0.1095 is below the 0.68 supporting threshold).	cspec pm5_candidates clinvar hci_prior PMID:18033691 PMID:19389263 PMID:21153778
PM6	N/A	Not applicable: assumed-de-novo evidence is scored within the PS2 points system under the MSH6 VCEP, not as PM6.	cspec
PP1	Not assessed	Not assessed: no co-segregation or pedigree data were available to compute a segregation likelihood ratio.	cspec clinvar PMID:18033691 PMID:18809606
PP2	N/A	Not applicable: the MSH6 VCEP explicitly does not use PP2.	cspec
PP3	Not met	Not met: the HCI prior probability of pathogenicity is 0.1095, far below the 0.68 supporting threshold, and SpliceAI max delta 0.02 is below 0.2.	cspec vcep_hci_priors_msh6 hci_prior spliceai revel bayesdel
PP4	Not assessed	Not assessed: no tumor MSI or MMR immunohistochemistry data were available for carriers of this variant.	cspec PMID:18033691 PMID:18809606
PP5	Not met	Not met: the only expert-panel classification for this variant is InSiGHT Likely Benign, which supports the benign direction (BP6), not PP5.	clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF 0.00226% is roughly 100-fold below the 0.22% BA1 threshold.	gnomad_v4 cspec
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF 0.00226% is about 10-fold below the 0.022% BS1 threshold.	gnomad_v4 cspec PMID:18033691
BS2	Not met	Not met: no in-trans co-occurrence with a pathogenic MSH6 variant is documented; gnomAD reports 0 homozygotes.	PMID:18033691 gnomad_v4 cspec
BS3	Not assessed	Not assessed: assays indicate proficient MMR activity, but the calibrated FOP values and mRNA-based assay evidence the VCEP requires were unavailable.	clinvar spliceai vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart PMID:18033691
BS4	Not assessed	Not assessed: no documented non-segregation exists to compute a lack-of-segregation likelihood ratio.	cspec clinvar PMID:18033691
BP1	N/A	Not applicable: missense is an established disease mechanism in MSH6, and the VCEP does not use BP1.	cspec
BP2	N/A	Not applicable: the MSH6 VCEP uses BS2 instead of BP2 for in-trans co-occurrence evidence.	cspec PMID:18033691
BP3	N/A	Not applicable: the VCEP does not use BP3, and this missense is not an in-frame indel in a repetitive region.	cspec PMID:18033691
BP4	Met	Met (supporting): HCI prior probability of pathogenicity 0.1095 is below the 0.11 BP4 threshold. Flagged for human review: the value sits only 0.0005 below the cutoff and should be re-confirmed against HCI PRIORS.	hci_prior vcep_hci_priors_msh6 cspec spliceai
BP5	Not assessed	Not assessed: no tumor MSI/MSS or MMR immunohistochemistry data were available to count MSS tumors in carriers.	cspec PMID:18033691 PMID:18809606
BP6	Met	Met (supporting benign): the InSiGHT expert panel classified this variant Likely Benign (ClinVar 3-star expert-panel review).	clinvar
BP7	N/A	Not applicable: BP7 applies only to synonymous or intronic variants, and c.1403G>A is a missense substitution.	cspec spliceai

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