Variant classification summary

NM_000179.3:c.187T>C

MSH6 · NP_000170.1:p.(Ser63Pro) · NM_000179.3

GRCh37: chr2:48010559 T>C · GRCh38: chr2:47783420 T>C

Gene: MSH6 Transcript: NM_000179.3

Final call

Likely Benign

BS1 strong BP4 supporting

Variant details

Gene

MSH6

Transcript

NM_000179.3

Protein

NP_000170.1:p.(Ser63Pro)

gnomAD AF

3.4420126771974604e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BS1 Strong: gnomAD v4.1 grpmax allele frequency of 0.00055895 meets the MSH6 frequency interval.

2

BP4 Supporting: MSH6 HCI prior probability of pathogenicity is 0.0027, below the <0.11 threshold.

Final determination: InSiGHT MSH6 Version 2.0 Rule18 combines one Benign Strong criterion with one Benign Supporting criterion to classify the variant as Likely Benign.

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.187T>C is a missense change, p.Ser63Pro, not a truncating or canonical splice variant eligible for PVS1.	cspec pvs1_variant_assessment
PS1	Not assessed	Not assessed: no verified alternate-nucleotide p.Ser63Pro comparator was identified, and the same-residue search reported zero candidates with an HTTP 429 retrieval error.	cspec pm5_candidates
PS2	Not assessed	Not assessed: no variant-specific proband, parental-confirmation, tumor, or de novo-point evidence is available for the PS2 thresholds.	cspec
PS3	Not assessed	Not assessed: no variant-specific functional assay result or calibrated functional odds are available for c.187T>C (p.Ser63Pro).	cspec
PS4	N/A	Not applicable: the MSH6 VCEP explicitly excludes PS4 from MMR variant classification when tumor IHC evidence is evaluated under PP4.	cspec
PM1	N/A	Not applicable: the governing MSH6 VCEP specification explicitly designates PM1 as Not Applicable, and no MSH6 domain_tables entry is present.	cspec vcep_mmr_functional_domains
PM2	Not met	Not met: gnomAD v4.1 total allele frequency is 0.0000344201, exceeding the MSH6 PM2 threshold of 0.00002.	cspec gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband observation, pathogenic MSH6 allele, or confirmed in-trans phase is documented, so PM3 points cannot be assigned.	cspec
PM4	N/A	Not applicable: the MSH6 VCEP designates PM4 as not applicable, and c.187T>C is a missense substitution with no protein-length change.	cspec
PM5	Not assessed	Not assessed: the p.Ser63Pro comparator search found zero same-residue candidates and an HTTP 429 error, so the required VCEP comparator and PP3 prerequisite remain unverified.	cspec pm5_candidates
PM6	N/A	Not applicable: the MSH6 VCEP explicitly excludes PM6 and directs assumed de novo observations to point-based PS2.	cspec
PP1	Not assessed	Not assessed: no variant-specific pedigree, meioses, relative genotypes, or Bayes likelihood ratio is available for the PP1 thresholds.	cspec
PP2	N/A	Not applicable: the governing MSH6 VCEP specification explicitly designates PP2 as Not Applicable.	cspec
PP3	Not met	Not met: MSH6 HCI prior probability 0.0027 is below the >0.68 PP3-supporting threshold.	cspec vcep_hci_priors_msh6 hci_prior
PP4	Not assessed	Not assessed: no variant-specific MSI-H tumor count or MSH6-consistent IHC result is available to compare with the VCEP's PP4 thresholds.	cspec PMID:22167527 PMID:25452455
PP5	N/A	Not applicable: the MSH6 VCEP excludes PP5, and ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic assertion.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax filtering allele frequency is 0.00055895, below the MSH6 BA1 threshold of 0.0022.	cspec gnomad_v4
BS1	Met	Met, strong: gnomAD v4.1 grpmax filtering allele frequency 0.00055895 falls between the MSH6 BS1 thresholds 0.00022 and 0.0022.	cspec gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports zero homozygotes, but no qualifying in-trans co-occurrence, cancer age, CMMRD, or phase data are available.	cspec gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific proficient-function assay result or calibrated functional odds <=0.05 are available for c.187T>C (p.Ser63Pro).	cspec
BS4	Not assessed	Not assessed: no variant-specific non-segregation pedigree data or combined Bayes likelihood ratio is available for the BS4 thresholds.	cspec
BP1	N/A	Not applicable: the governing MSH6 VCEP specification explicitly designates BP1 as Not Applicable.	cspec
BP2	N/A	Not applicable: the MSH6 VCEP explicitly designates BP2 as Not Applicable for this gene-specific framework.	cspec
BP3	N/A	Not applicable: the MSH6 VCEP designates BP3 as not applicable, and c.187T>C causes missense p.Ser63Pro rather than an in-frame indel.	cspec
BP4	Met	Met, supporting: MSH6 HCI prior probability 0.0027 is below the <0.11 BP4 threshold.	cspec vcep_hci_priors_msh6 hci_prior
BP5	Not assessed	Not assessed: no variant-specific MSS, preserved/discordant MMR IHC, BRAF V600E, or MLH1 methylation findings are documented for the BP5 thresholds.	cspec
BP6	N/A	Not applicable: the MSH6 VCEP excludes BP6, and no exact-variant ClinVar expert-panel Benign or Likely benign assertion exists.	cspec clinvar
BP7	N/A	Not applicable: c.187T>C is a missense variant encoding p.Ser63Pro, not a synonymous variant.	cspec

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