Variant classification summary

NM_000179.3:c.4002-17T>C

MSH6 · NP_000170.1:p.? · NM_000179.3

GRCh37: chr2:48033901 T>C · GRCh38: chr2:47806762 T>C

Gene: MSH6 Transcript: NM_000179.3

Final call

PM2 supporting BP4 supporting

Variant details

Gene

MSH6

Transcript

NM_000179.3

Protein

NP_000170.1:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The MSH6 c.4002-17T>C (NP_000170.1:p.?) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.

2

This variant is absent from gnomAD v4.1, gnomAD v2.1, and gnomAD-Canada, supporting rarity below the MSH6 PM2 threshold of less than 0.00002.

3

SpliceAI predicts no significant splice impact, with a maximum delta score of 0.04, which is below the MSH6 BP4 threshold of less than or equal to 0.1 and below the PP3 threshold of greater than or equal to 0.2 for non-canonical splice variants.

Final determination: Rule31 in the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MSH6 Version 2.0.0 v2.0.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Uncertain Significance - Conflicting Evidence.

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
BA1	Not met	This variant is absent from gnomAD v4.1 and therefore does not meet the MSH6 BA1 threshold of filtering allele frequency greater than or equal to 0.0022 (0.22%).	gnomad_v4 cspec
BS2	Not assessed	No co-occurrence data in trans with a known pathogenic MSH6 variant in an older individual without features of constitutional mismatch repair deficiency were identified, so BS2 could not be assessed.	cspec vcep_table_for_cmmrd_diagnosis
BP6	N/A	BP6 is not used in the MSH6 expert-panel framework.	cspec
PP4	Not assessed	No tumor microsatellite instability or mismatch repair immunohistochemistry data were identified, so PP4 could not be assessed.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 could not be assessed.	cspec
BS1	Not met	This variant is absent from gnomAD v4.1 and therefore does not meet the MSH6 BS1 frequency range of greater than or equal to 0.00022 and less than 0.0022.	gnomad_v4 cspec
BP7	Not met	This is an intronic variant at c.4002-17, which is 17 nucleotides from the exon boundary and does not meet the MSH6 BP7 distance requirement for variants at or beyond -21 or +7.	cspec
PP2	N/A	PP2 is not used in the MSH6 expert-panel framework.	cspec
BP3	N/A	BP3 is not used in the MSH6 expert-panel framework.	cspec
BP1	N/A	BP1 is not used in the MSH6 expert-panel framework.	cspec
BS3	Not assessed	No variant-specific RNA or functional assay data showing normal splicing or retained function were identified, so BS3 could not be assessed.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart
PM2	Met	This variant is absent from gnomAD v4.1, gnomAD v2.1, and gnomAD-Canada. Its observed population frequency is therefore below the MSH6 PM2 threshold of less than 0.00002 (fewer than 1 in 50,000 alleles), supporting rarity.	gnomad_v4 gnomad_v2 gnomad_canada cspec
BP4	Met	SpliceAI predicts no significant splice impact for this intronic variant, with a maximum delta score of 0.04. This is below the MSH6 BP4 threshold of less than or equal to 0.1 and supports no predicted splicing effect.	spliceai cspec
PS1	Not assessed	No pathogenic or likely pathogenic comparator affecting the same non-canonical splice nucleotide was identified in the available evidence, so PS1 could not be applied.	clinvar cspec
PS2	Not assessed	No de novo data were identified for this variant, so PS2 could not be assessed.	cspec
BP5	Not assessed	No tumor data showing microsatellite-stable disease, retained mismatch repair protein expression, or gene-inconsistent loss of mismatch repair proteins were identified, so BP5 could not be assessed.	cspec
PVS1	Not met	Although loss of function is an established disease mechanism for MSH6, this variant is a non-canonical intronic change at c.4002-17 and does not fall within the default PVS1 null-variant categories. No patient RNA evidence showing a confirmed splice defect was identified, so PVS1 is not met.	cspec pvs1_gene_context pvs1_variant_assessment
PP5	N/A	PP5 is not used in the MSH6 expert-panel framework.	cspec
BP2	N/A	BP2 is not used in the MSH6 expert-panel framework.	cspec
PS4	N/A	PS4 is not used in the MSH6 expert-panel framework.	cspec
PM4	N/A	PM4 is not used in the MSH6 expert-panel framework.	cspec
PS3	Not assessed	No calibrated functional or RNA assay evidence showing a damaging effect was identified for this variant, so PS3 could not be assessed.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart
PP3	Not met	SpliceAI does not support a predicted splice defect for this non-canonical intronic variant. The maximum delta score is 0.04, which is below the MSH6 PP3 threshold of greater than or equal to 0.2.	spliceai cspec
PM6	N/A	PM6 is not used in the MSH6 expert-panel framework.	cspec
PM1	N/A	PM1 is not used in the MSH6 expert-panel framework.	cspec
PM3	Not assessed	No data were identified showing this variant in trans with another pathogenic MSH6 variant in a constitutional mismatch repair deficiency setting, so PM3 could not be assessed.	cspec vcep_table_for_cmmrd_diagnosis
BS4	Not assessed	No non-segregation data were identified for this variant, so BS4 could not be assessed.	cspec
PM5	N/A	The MSH6 PM5 rule is a classic same-residue missense criterion. This variant is intronic and not missense-like, so PM5 is not applicable.	pm5_candidates cspec

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