MSH6 c.2091T>C, p.(Asp697=)

Rule

Absent/extremely rare allele frequency < 0.00002 (<1 in 50,000 alleles) in gnomAD v4 dataset.

Evidence considered

• gnomAD v4.1: absent

Sources

Rule

For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score <= 0.1.

Evidence considered

• SpliceAI max delta score 0.02

Sources

Rule

A synonymous (silent) or intronic variant at or beyond -21/+7 (5′/3′ exonic). Variants may satisfy both BP7 and BP4.

Evidence considered

• Synonymous change p.(Asp697=)
• c.2091 lies within exon 4 (c.628-c.3172)

Sources

Rule

PVS1 applies to defined MSH6 loss-of-function variant classes or confirmed splice-defect variants meeting VCEP requirements.

Evidence considered

• Variant class: synonymous
• PVS1 variant bucket: other
• Canonical splice consensus: false

Still missing

• Variant-specific RNA evidence would be needed to revisit loss-of-function splicing

Sources

Rule

PP3 applies to missense variants meeting HCI-prior thresholds or non-canonical splice variants with SpliceAI delta score >= 0.2.

Evidence considered

• Variant consequence: synonymous
• SpliceAI max delta score 0.02

Sources

Rule

GnomAD v4 Grpmax filtering allele frequency >= 0.0022 (0.22%) and variant is excluded as founder pathogenic variant.

Evidence considered

• gnomAD v4.1: absent

Sources

Rule

GnomAD v4 Grpmax filtering allele frequency >= 0.00022 and < 0.0022 (0.022-0.22%) and variant is excluded as founder pathogenic variant.

Evidence considered

• gnomAD v4.1: absent

Sources

Rule

Variants affecting the same non-canonical splice nucleotide as a confirmed pathogenic or likely pathogenic splice variant with similar or worse SpliceAI prediction.

Evidence considered

• SpliceAI max delta score 0.02

Still missing

• Variant-level evidence for an established pathogenic or likely pathogenic comparator at the same non-canonical splice nucleotide

Sources

Rule

De novo point-based framework for Lynch syndrome-associated tumors.

Still missing

• Documented de novo occurrence with tumor context and parentage confirmation

Sources

Rule

Calibrated functional assays with functional odds for pathogenicity above VCEP thresholds, or qualifying RNA evidence showing abnormal splicing.

Still missing

• Variant-specific damaging functional assay data
• Variant-specific RNA splicing assay data

Sources

Rule

Point-based co-occurrence framework in patients with clinical features consistent with CMMRD.

Still missing

• Genotype/phase data
• Clinical features relevant to CMMRD

Sources

Rule

Missense change at an amino acid residue where a different missense change was classified by this VCEP as pathogenic or likely pathogenic on the protein level and not due to aberrant splicing.

Still missing

• A qualifying pathogenic or likely pathogenic missense comparator would be required if residue-based evaluation were considered

Sources

Rule

Co-segregation with disease in pedigree(s) with a combined Bayes likelihood ratio above VCEP thresholds.

Still missing

• Family segregation data with Bayes likelihood ratio

Sources

Rule

Tumor MSI-H and/or loss of MMR protein expression consistent with the variant location, with strength based on the number of informative tumors.

Still missing

• MSI results
• MMR immunohistochemistry results
• Phenotype details and number of informative tumors/families

Sources

Rule

Co-occurrence in trans with a known pathogenic sequence variant in the same gene in a patient with colorectal cancer after age 45 or another LS cancer above the median age of onset, without evidence of CMMRD.

Still missing

• Phase-confirmed co-occurrence data
• Clinical information addressing CMMRD features

Sources

Rule

For synonymous substitutions and intronic variants, BS3 requires no associated mRNA aberration in laboratory assays conducted with nonsense-mediated decay inhibition, or other qualifying benign functional evidence.

Still missing

• Variant-specific RNA assay data
• Variant-specific calibrated functional assay data

Sources

Rule

Lack of co-segregation with disease in pedigree(s) with a combined Bayes likelihood ratio below benign thresholds.

Still missing

• Family segregation data with Bayes likelihood ratio showing non-segregation

Sources

Rule

Benign evidence based on tumors inconsistent with the gene involved or alternative molecular explanations.

Still missing

• Tumor MSI/IHC data
• BRAF or MLH1 methylation data where relevant
• Additional molecular findings

Sources