MSH6 c.199C>A, p.(Pro67Thr)

Rule

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

Evidence considered

• gnomAD v4.1 total AF 6.66082e-07
• MSH6 PM2 threshold is <0.00002

Sources

Rule

MSH6 PVS1 applies to qualifying truncating, canonical splice, large genomic, or confirmed splice-defect variants under the VCEP rule.

Evidence considered

• MSH6 loss of function is an established disease mechanism in the VCEP framework
• variant-level PVS1 assessment classifies this missense change outside generic null-variant buckets
• NM_000179.3:c.199C>A predicts p.(Pro67Thr)

Still missing

• No RNA evidence was identified showing that this specific allele causes a qualifying splicing defect.

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 total AF 6.66082e-07
• highest observed population AF 8.86721e-07 in non-Finnish Europeans
• MSH6 BA1 threshold is >=0.0022

Sources

Rule

GnomAD v4 grpmax filtering allele frequency >= 0.00022 and < 0.0022, and variant is excluded as a founder pathogenic variant.

Evidence considered

• gnomAD v4.1 highest observed population AF 8.86721e-07 in non-Finnish Europeans
• MSH6 BS1 range is >=0.00022 and <0.0022

Sources

Rule

A synonymous (silent) or intronic variant at or beyond -21/+7 (5′/3′ exonic).

Evidence considered

• NM_000179.3:c.199C>A predicts p.(Pro67Thr) missense change

Sources

Rule

Same amino acid change as a previously established pathogenic or likely pathogenic variant under the VCEP conditions.

Evidence considered

• No matching same-amino-acid comparator was identified in the reviewed VCEP materials

Still missing

• No VCEP-established alternate nucleotide change encoding the same amino acid substitution was identified.
• No qualifying pathogenic or likely pathogenic splice comparator at the same non-canonical splice nucleotide was identified.

Sources

Rule

De novo points reaching the VCEP-defined threshold.

Evidence considered

• MSH6 VCEP PS2 requires scored de novo evidence

Still missing

• No trio-tested or parentage-confirmed de novo case was identified.
• No de novo point total was identified.

Sources

Rule

Calibrated pathogenic functional odds or MMR function defect following the functional assay flowchart.

Evidence considered

• No variant-specific functional assay evidence was identified in the reviewed materials
• MSH6 VCEP PS3 requires pathogenic functional assay evidence

Still missing

• No calibrated pathogenic functional odds were identified for this variant.
• No variant-specific MMR-deficient protein or RNA assay result was identified.

Sources

Rule

Points-based PM3 application under the MSH6 VCEP framework.

Evidence considered

• MSH6 VCEP PM3 requires scored observations for recessive/CMMRD context

Still missing

• No confirmed phase information was identified.
• No CMMRD-related point assignment data were identified.

Sources

Rule

Different pathogenic or likely pathogenic missense change at the same residue under the VCEP conditions.

Evidence considered

• No qualifying codon 67 comparator was identified in the reviewed VCEP materials

Still missing

• No qualifying pathogenic or likely pathogenic missense comparator at Pro67 was identified.
• PP3 was not met from the available missense-specific VCEP evidence.

Sources

Rule

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

Evidence considered

• MSH6 VCEP PP1 requires segregation quantified by Bayes likelihood ratio

Still missing

• No pedigree data were identified.
• No Bayes likelihood ratio for segregation was identified.

Sources

Rule

Missense variant with HCI prior probability for pathogenicity >0.68, or non-canonical splice variant with SpliceAI >=0.2.

Evidence considered

• SpliceAI max delta score 0.00
• REVEL score 0.161
• BayesDel score -0.32103
• MSH6 VCEP PP3 missense rule uses HCI prior probability

Still missing

• No HCI prior probability was identified for this missense variant.

Sources

Rule

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

Evidence considered

• MSH6 VCEP PP4 requires MSI-H and/or loss of MMR protein expression consistent with the gene

Still missing

• No MSI-H tumor data were identified.
• No mismatch repair protein expression data were identified.

Sources

Rule

Co-occurrence in trans with a known pathogenic sequence variant in the same gene in a patient meeting the VCEP clinical conditions and without evidence of CMMRD.

Evidence considered

• MSH6 VCEP BS2 requires confirmed in trans co-occurrence plus specific clinical context

Still missing

• No confirmed in trans co-occurrence data were identified.
• No case-level clinical information addressing the VCEP CMMRD exclusions was identified.

Sources

Rule

Calibrated benign functional odds or variant-specific proficient function in protein and mRNA-based laboratory assays per the MMR functional assay flowchart.

Evidence considered

• No variant-specific functional assay evidence was identified in the reviewed materials
• MSH6 VCEP BS3 requires benign functional assay evidence

Still missing

• No calibrated benign functional odds were identified for this variant.
• No variant-specific proficient protein or RNA assay result was identified.

Sources

Rule

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

Evidence considered

• MSH6 VCEP BS4 requires quantified non-segregation evidence

Still missing

• No informative family data were identified.
• No Bayes likelihood ratio for non-segregation was identified.

Sources

Rule

Missense variant with HCI prior probability of pathogenicity <0.11, or for intronic/synonymous variants SpliceAI <=0.1.

Evidence considered

• SpliceAI max delta score 0.00
• REVEL score 0.161
• BayesDel score -0.32103
• MSH6 VCEP BP4 missense rule uses HCI prior probability

Still missing

• No HCI prior probability was identified for this missense variant.

Sources

Rule

Tumor features inconsistent with the gene involved, or qualifying BRAF/MLH1 methylation findings under the VCEP rule.

Evidence considered

• MSH6 VCEP BP5 requires specific tumor findings inconsistent with Lynch syndrome due to the tested gene

Still missing

• No tumor molecular data relevant to BP5 were identified.
• No BRAF V600E or MLH1 methylation data were identified.

Sources