Variant classification summary

NM_000179.2:c.1483C>T

MSH6 · NP_000170.1:p.(Arg495Ter) · NM_000179.2

GRCh37: chr2:48026605 C>T · GRCh38: chr2:47799466 C>T

Gene: MSH6 Transcript: NM_000179.2

Final call

Pathogenic

PVS1 very strong PM2 supporting PP5 supporting

Variant details

Gene

MSH6

Transcript

NM_000179.2

Protein

NP_000170.1:p.(Arg495Ter)

gnomAD AF

1.8588627477709137e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000179.2:c.1483C>T (p.Arg495Ter) is a nonsense variant in MSH6 that introduces a premature termination codon at position 495, well below the VCEP cutoff of codon 1341, qualifying for PVS1 at Very Strong strength.

2

The variant is extremely rare in population databases with an allele frequency of 1.86e-06 in gnomAD v4.1 (3/1,613,890 alleles, 0 homozygotes), meeting the MSH6 VCEP PM2_Supporting threshold of <0.00002.

3

This variant has been reported in ClinVar (VariationID 89197) as Pathogenic by the InSiGHT expert panel (3-star review status) and by 22 clinical laboratories, supporting PP5 at Supporting strength.

4

The variant was identified in one Brazilian Lynch syndrome proband (PMID:26437257, patient ID-152) with colon cancer at age 59 meeting Bethesda guideline criteria; no MSI, IHC, or co-segregation data were available.

5

Applying the ClinGen InSiGHT MSH6 VCEP v2.0 combination rules: PVS1 (Very Strong) + PM2 (Supporting) + PP5 (Supporting) meets Rule 4 (1 Very Strong + ≥2 Supporting) for a classification of Pathogenic.

Final determination: Rule4 in the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MSH6 Version 2.0 v2.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Pathogenic.

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	NM_000179.2:c.1483C>T is a nonsense variant that introduces a premature termination codon (p.Arg495Ter) at codon 495, which is well below the VCEP threshold of codon 1341 for MSH6. Under the ClinGen InSiGHT MSH6 VCEP v2.0 PVS1 rule, nonsense variants introducing PTC at or before codon 1341 qualify for PVS1 at Very Strong strength. Loss of function is an established disease mechanism for MSH6 in Lynch syndrome.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not met	PS1 requires a different nucleotide change encoding the same amino acid change (p.Arg495Ter) previously classified as Pathogenic by this VCEP. No evidence of an alternate nucleotide substitution creating the same stop codon (e.g., c.1483C>G or c.1484G>A) having been classified as Pathogenic by the InSiGHT VCEP was identified.	cspec
PS2	Not met	PS2 requires de novo occurrence data with confirmed maternity/paternity. No de novo observations for NM_000179.2:c.1483C>T were identified in any reviewed literature or database.
PS3	Not met	PS3 requires variant-specific experimental functional data or systematic characterization of the variant position through calibrated functional assays as defined by the VCEP MMR functional assay documentation. Although c.1483C>T is a nonsense variant predicted to result in complete loss of function via NMD, no direct functional assay data for this exact variant was identified. The paper by Carneiro da Silva et al. (PMID:26437257) reports the variant in a Lynch syndrome patient but does not include functional studies. The predicted loss-of-function effect is already captured by PVS1.	vcep_functional_assay_svi_documentation_mmr PMID:26437257
PS4	N/A	PS4 is marked Not Applicable by the MSH6 VCEP v2.0.	cspec
PS5	Not met	PS5 is not defined by the MSH6 VCEP. The ClinVar entry (VariationID 89197) is classified as Pathogenic by the InSiGHT expert panel, which is the same body that authored this VCEP. Citing the VCEP's own expert panel classification as external reputable-source evidence would be circular. No independent external source distinct from the VCEP was identified.	clinvar cspec
PM1	N/A	PM1 is marked Not Applicable by the MSH6 VCEP v2.0.	cspec
PM2	Met	Under MSH6 VCEP v2.0, PM2 at Supporting strength applies when the variant is absent or extremely rare in gnomAD v4 with an allele frequency below 0.00002 (<1 in 50,000 alleles). This variant has an allele frequency of 1.86e-06 in gnomAD v4.1 (3/1,613,890 alleles, 0 homozygotes), which is well below the threshold. It is also extremely rare in gnomAD v2.1 (1/251,182 alleles).	gnomad_v4 gnomad_v2 cspec
PM5	N/A	The variant is a nonsense change (p.Arg495Ter), not a missense substitution. PM5 under VCEP applies only to missense changes at amino acid residues where a different missense change was classified as Pathogenic or Likely Pathogenic. Additionally, the pm5_candidates module confirms no eligible same-residue missense comparators exist.	pm5_candidates cspec
PM6	N/A	PM6 is marked Not Applicable by the MSH6 VCEP v2.0.	cspec
PP1	Not met	PP1 requires co-segregation data with a Bayes Likelihood Ratio meeting VCEP thresholds. No pedigree or co-segregation data were available for this variant. The paper by Carneiro da Silva et al. (PMID:26437257) reports the variant in a single patient (ID-152, colon cancer at age 59, meeting Bethesda guideline) but provides no multi-generational co-segregation analysis.	PMID:26437257 cspec
PP2	N/A	PP2 is marked Not Applicable by the MSH6 VCEP v2.0.	cspec
PP3	Not met	PP3 under MSH6 VCEP v2.0 requires either: (a) a missense variant with HCI prior probability of pathogenicity >0.68, or (b) a predicted splice defect at a non-canonical splice site with SpliceAI delta score ≥0.2. This is a nonsense variant, not a missense substitution, so HCI prior lookup is not applicable (confirmed absent from the MSH6 HCI-PRIORS table). SpliceAI predicts no splicing impact (max delta score = 0.04). Neither PP3 pathway is satisfied.	spliceai vcep_hci_priors_msh6 cspec
PP4	Not met	PP4 under MSH6 VCEP v2.0 requires MSI-H colorectal or endometrial tumors and/or loss of MMR protein expression consistent with the variant location. The single reported proband (Carneiro da Silva et al., PMID:26437257, patient ID-152) had colon cancer at age 59 meeting Bethesda guideline, but no MSI or IHC data were reported for this patient. Without tumor phenotype data, PP4 cannot be applied.	PMID:26437257 cspec
PP5	Met	Expert panel International Society for Gastrointestinal Hereditary Tumours (InSiGHT) classified as Pathogenic.	clinvar
BA1	Not met	BA1 under MSH6 VCEP v2.0 requires gnomAD v4 Grpmax filtering allele frequency ≥ 0.0022 (0.22%) and exclusion as a founder pathogenic variant. This variant has an allele frequency of 1.86e-06 in gnomAD v4.1, far below the BA1 threshold.	gnomad_v4 cspec
BS1	Not met	BS1 under MSH6 VCEP v2.0 requires gnomAD v4 Grpmax filtering allele frequency ≥ 0.00022 and < 0.0022 (0.022%–0.22%). This variant has an allele frequency of 1.86e-06 in gnomAD v4.1, below the BS1 lower threshold.	gnomad_v4 cspec
BS2	Not met	BS2 under MSH6 VCEP v2.0 requires co-occurrence in trans with a known pathogenic variant in a patient with colorectal cancer after age 45 without clinical manifestations of CMMRD. No such co-occurrence data were identified.	cspec
BS3	Not met	BS3 under MSH6 VCEP v2.0 requires calibrated functional assays demonstrating functional odds for pathogenicity ≤ 0.05 (Strong) or between 0.05 and 0.48 (Supporting), or variant-specific proficient function in protein/mRNA-based assays. No benign functional data were identified for this variant. The variant is a nonsense mutation predicted to cause complete loss of function, which is inconsistent with a BS3 determination.	vcep_functional_assay_svi_documentation_mmr cspec
BS4	Not met	BS4 under MSH6 VCEP v2.0 requires lack of co-segregation with disease in pedigrees with a combined Bayes Likelihood Ratio meeting specified thresholds. No segregation data were available for this variant.	cspec
BP1	N/A	BP1 is marked Not Applicable by the MSH6 VCEP v2.0.	cspec
BP2	N/A	BP2 is marked Not Applicable by the MSH6 VCEP v2.0.	cspec
BP4	N/A	BP4 under MSH6 VCEP v2.0 applies only to missense variants with HCI prior probability <0.11 or intronic/synonymous variants with SpliceAI delta score ≤0.1. This is a nonsense variant in exon 4; neither BP4 pathway is applicable.	spliceai vcep_hci_priors_msh6 cspec
BP5	Not met	BP5 under MSH6 VCEP v2.0 requires tumors with MSS and/or no loss of MMR protein expression inconsistent with the gene, or BRAF V600E/MLH1 methylation with MSI-H. No tumor phenotype data (MSI status or IHC) were reported for this variant. The single reported proband (PMID:26437257) had no MSI or IHC data available.	PMID:26437257 cspec
BP6	Not met	BP6 applies when a reputable source classifies the variant as benign. ClinVar VariationID 89197 is classified as Pathogenic by the InSiGHT expert panel and 22 clinical laboratories — not benign. The BP6 override rule for ClinVar 3-star expert panels applies only when the classification direction is benign; here the classification is Pathogenic.	clinvar cspec
BP7	N/A	BP7 under MSH6 VCEP v2.0 applies only to synonymous (silent) or intronic variants at or beyond positions -21/+7. This is a nonsense variant in exon 4, creating a premature termination codon. BP7 does not apply.	cspec
BP3	N/A	In-frame deletion/insertion criterion; not applicable to this substitution variant.
PM3	N/A	Biallelic/recessive criterion; skipped per assessment instructions.
PM4	N/A	In-frame deletion/insertion criterion; not applicable to this substitution variant.

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