Variant classification summary

NM_000179.3:c.2731C>T

MSH6 · NP_000170.1:p.(Arg911Ter) · NM_000179.3

GRCh37: chr2:48027853 C>T · GRCh38: chr2:47800714 C>T

Gene: MSH6 Transcript: NM_000179.3

Final call

Pathogenic

PVS1 very strong PM2 supporting PP4 moderate PP5 supporting

Variant details

Gene

MSH6

Transcript

NM_000179.3

Protein

NP_000170.1:p.(Arg911Ter)

gnomAD AF

1.3631372976670525e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): Nonsense variant p.Arg911Ter creates a premature stop codon before the MSH6 codon 1341 cutoff.

2

PM2 (Supporting): gnomAD v4.1 Grpmax filtering allele frequency is 8.78e-06, below the 0.00002 threshold.

3

PP4 (Moderate): This exact variant occurred in two independent endometrial cancer tumors that were MSI-H.

4

PP5 (Supporting): The InSiGHT expert panel classified this exact variant as Pathogenic.

5

Overall classification: Pathogenic under MSH6 VCEP Rule 4, combining one Very Strong criterion with at least two Supporting criteria.

Final determination: MSH6 VCEP Version 2.0 Rule4 is satisfied by one Pathogenic Very Strong criterion and at least two Pathogenic Supporting criteria, resulting in a Pathogenic classification.

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	Met	Met (Very Strong): Nonsense variant p.Arg911Ter creates a premature stop codon before the MSH6 codon 1341 cutoff.	cspec clinvar
PS1	N/A	Not applicable: This is a nonsense variant, not a missense change or specified non-canonical splice variant.	cspec
PS2	Not assessed	Not assessed: No parental testing, confirmed de novo status, or qualifying tumor evidence was available.	cspec
PS3	Not assessed	Not assessed: No variant-specific functional assay or calibrated functional odds were available.	cspec clinvar
PS4	N/A	Not applicable: The MSH6 expert-panel specification designates PS4 as not applicable.	cspec
PM1	N/A	Not applicable: The MSH6 expert-panel specification designates PM1 as not applicable.	cspec
PM2	Met	Met (Supporting): gnomAD v4.1 Grpmax filtering allele frequency is 8.78e-06, below the 0.00002 threshold.	cspec gnomad_v4
PM3	Not assessed	Not assessed: No second pathogenic MSH6 variant, phase information, or qualifying CMMRD features were available.	cspec
PM4	N/A	Not applicable: The MSH6 expert-panel specification designates PM4 as not applicable, and this is a nonsense variant.	cspec
PM5	N/A	Not applicable: This is a nonsense variant, whereas PM5 requires a different pathogenic missense change at the same residue.	cspec
PM6	N/A	Not applicable: The MSH6 specification designates PM6 as not applicable and routes unconfirmed de novo cases through PS2.	cspec
PP1	Not assessed	Not assessed: No variant-specific pedigree, cosegregation data, or Bayes likelihood ratio was available.	cspec
PP2	N/A	Not applicable: The MSH6 expert-panel specification designates PP2 as not applicable, and this is a nonsense variant.	cspec
PP3	Not met	Not met: SpliceAI maximum delta score is 0.005, below the required >=0.2 splice-impact threshold.	cspec spliceai
PP4	Met	Met (Moderate): This exact variant occurred in two independent endometrial cancer tumors that were MSI-H.	cspec PMID:12732731 PMID:15098177
PP5	Met	Met (Supporting): The InSiGHT expert panel classified this exact variant as Pathogenic.	clinvar
BA1	Not met	Not met: gnomAD v4.1 Grpmax filtering allele frequency is 8.78e-06, below the 0.0022 threshold.	cspec gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 Grpmax filtering allele frequency is 8.78e-06, below the 0.00022 threshold.	cspec gnomad_v4
BS2	Not assessed	Not assessed: No confirmed in-trans pathogenic variant, phase, cancer history, or CMMRD-exclusion evidence was available.	cspec
BS3	Not assessed	Not assessed: No variant-specific functional assay or calibrated evidence of proficient function was available.	cspec clinvar
BS4	Not assessed	Not assessed: No variant-specific non-segregation observations, pedigree data, or Bayes likelihood ratio was available.	cspec
BP1	N/A	Not applicable: The MSH6 expert-panel specification designates BP1 as not applicable, and this is a nonsense variant.	cspec
BP2	N/A	Not applicable: The MSH6 specification designates BP2 as not applicable and directs evaluation of this evidence through BS2.	cspec
BP3	N/A	Not applicable: The MSH6 expert-panel specification designates BP3 as not applicable, and this is a nonsense variant.	cspec
BP4	N/A	Not applicable: This nonsense variant is neither a missense variant nor an intronic or synonymous variant covered by BP4.	cspec bayesdel
BP5	Not met	Not met: No qualifying MSS or MMR-retained tumors were identified; reported tumors were MSI-H.	cspec PMID:12732731 PMID:15098177
BP6	N/A	Not applicable: The MSH6 expert-panel specification designates BP6 as not applicable, with no benign expert-panel classification present.	cspec clinvar
BP7	N/A	Not applicable: This coding nonsense variant is neither synonymous nor intronic, as required for BP7.	cspec

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