Variant classification summary

NM_000179.3:c.3674C>T

MSH6 · NP_000170.1:p.(Thr1225Met) · NM_000179.3

GRCh37: chr2:48033370 C>T · GRCh38: chr2:47806231 C>T

Gene: MSH6 Transcript: NM_000179.3

Final call

VUS

PP3 supporting PP4 supporting BS3 supporting BP5 supporting

Variant details

Gene

MSH6

Transcript

NM_000179.3

Protein

NP_000170.1:p.(Thr1225Met)

gnomAD AF

5.762324558903349e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PP3 (Supporting): HCI prior probability of pathogenicity 0.7336 falls in the VCEP's supporting band.

2

PP4 (Supporting): one endometrial tumor with the variant was MSI-H (3/5 unstable microsatellite markers).

3

BS3 (Supporting): a cell-free MMR complementation assay (PMID:22102614) found the variant repair proficient.

4

BP5 (Supporting): a parent and child each had an MSI-negative colorectal tumor at age 49.

5

Overall: VUS under VCEP Rule31, balancing two pathogenic-supporting (PP3, PP4) against two benign-supporting (BS3, BP5) criteria.

Final determination:

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 change (p.Thr1225Met) with no predicted splice impact (SpliceAI max delta 0.00), outside the PVS1 nonsense/frameshift/splice-site rule scope.	cspec spliceai
PS1	Not assessed	Not assessed: no alternate nucleotide change encoding the same p.Thr1225Met amino acid was identified in reviewed sources.	pm5_candidates
PS2	Not assessed	Not assessed: no documented de novo occurrence with confirmed parental testing or qualifying tumor context was available.	cspec
PS3	Not met	Not met: a cell-free MMR assay (PMID:22102614) found the variant repair proficient, the opposite of the damaging effect PS3 requires.	PMID:22102614 cspec
PS4	N/A	Not applicable: the InSiGHT MSH6 VCEP specification excludes case-control enrichment assessment (PS4) for this gene.	cspec
PM1	N/A	Not applicable: the MSH6 VCEP specification designates PM1 as not applicable for this gene.	cspec
PM2	Not met	Not met: gnomAD v4.1 allele frequency 0.0000576 exceeds the VCEP's <0.00002 PM2 threshold.	cspec gnomad_v4 PMID:17312306
PM3	Not assessed	Not assessed: no second pathogenic MSH6 variant with documented phase or CMMRD-consistent features was available.	cspec PMID:17312306 PMID:16885385 PMID:18566915
PM4	N/A	Not applicable: the MSH6 VCEP excludes PM4, and this missense produces no protein length change.	cspec
PM5	Not assessed	Not assessed: no other missense change at residue Thr1225 with a VCEP classification was identified.	pm5_candidates
PM6	N/A	Not applicable: the InSiGHT MSH6 specification does not permit PM6 at any strength.	cspec
PP1	Not assessed	Not assessed: segregation analysis was explicitly not possible, so no pedigree likelihood ratio is available.	cspec PMID:17312306 PMID:16885385 PMID:18566915
PP2	N/A	Not applicable: the MSH6 VCEP specification designates PP2 as not applicable for this gene.	cspec
PP3	Met	Met (Supporting): HCI prior probability of pathogenicity 0.7336 falls in the VCEP's supporting band (>0.68, ≤0.81).	cspec hci_prior vcep_hci_priors_msh6
PP4	Met	Met (Supporting): one endometrial tumor with the variant showed 3/5 unstable microsatellite markers (MSI-H), meeting the VCEP PP4 requirement.	cspec PMID:16885385
PP5	N/A	Not applicable: the MSH6 VCEP excludes PP5, and no expert-panel ClinVar submission exists for this variant.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 Grpmax FAF 0.00005137 is far below the ≥0.0022 BA1 threshold.	cspec gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 Grpmax FAF 0.00005137 falls below the 0.00022–0.0022 BS1 band.	cspec gnomad_v4
BS2	Not assessed	Not assessed: no in-trans co-occurrence with a pathogenic variant, phase, or CMMRD-exclusion evidence was available.	cspec
BS3	Met	Met (Supporting): a cell-free MMR complementation assay (PMID:22102614) found the variant repair proficient, matching the VCEP BS3 supporting rule.	PMID:22102614 cspec
BS4	Not assessed	Not assessed: no non-segregating pedigree or Bayes likelihood ratio against co-segregation is available.	cspec PMID:17312306
BP1	N/A	Not applicable: the MSH6 VCEP specification designates BP1 as not applicable for this gene.	cspec
BP2	N/A	Not applicable: the MSH6 VCEP designates BP2 not applicable, using BS2 in its place.	cspec
BP3	N/A	Not applicable: the MSH6 VCEP excludes BP3, and this missense is not an in-frame indel.	cspec
BP4	Not met	Not met: HCI prior probability 0.7336 is well above the <0.11 BP4 threshold.	cspec hci_prior vcep_hci_priors_msh6
BP5	Met	Met (Supporting): a parent and child each had an MSI-negative colorectal tumor at age 49, meeting VCEP BP5.	cspec PMID:17312306
BP6	N/A	Not applicable: the MSH6 VCEP excludes BP6, and no expert-panel submission exists for this variant.	cspec clinvar
BP7	N/A	Not applicable: BP7 covers only synonymous or deep intronic variants, and this is a missense change.	cspec

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