Variant classification summary

NM_000179.3:c.2091T>C

MSH6 · NP_000170.1:p.(Asp697=) · NM_000179.3

GRCh37: chr2:48027213 T>C · GRCh38: chr2:47800074 T>C

Gene: MSH6 Transcript: NM_000179.3

Final call

Likely Benign

BP7 supporting PM2 supporting BP4 supporting

Variant details

Gene

MSH6

Transcript

NM_000179.3

Protein

NP_000170.1:p.(Asp697=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The MSH6 c.2091T>C (p.Asp697=) variant has not been observed in somatic cancers in COSMIC.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, and its gnomAD v4.1 frequency is therefore below the MSH6 PM2_Supporting threshold of less than 0.00002.

3

This synonymous exon 4 variant is far from the splice junction boundaries used for MSH6 BP7, and SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.02, supporting BP7 and BP4 while arguing against PP3 or PVS1 based on the currently available evidence.

Final determination: Rule19 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 Likely Benign.

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, so it does not meet the MSH6 BA1 threshold of group maximum filtering allele frequency greater than or equal to 0.22%.	gnomad_v4 cspec
BS2	Not assessed	No co-occurrence data in trans with a known pathogenic MSH6 variant in an individual lacking clinical features of CMMRD were identified, so BS2 cannot be assessed from the available evidence.	cspec
BP6	N/A	BP6 is not used in the MSH6 VCEP framework.	cspec
PP4	Not assessed	No tumor microsatellite instability results, mismatch repair immunohistochemistry results, or phenotype data meeting the MSH6 PP4 thresholds were identified.	cspec
PP1	Not assessed	No segregation data were identified, so PP1 cannot be applied.	cspec
BS1	Not met	This variant is absent from gnomAD v4.1, so it does not meet the MSH6 BS1 threshold of group maximum filtering allele frequency greater than or equal to 0.00022 and less than 0.0022.	gnomad_v4 cspec
BP7	Met	This is a synonymous variant, NM_000179.3:p.(Asp697=), located in exon 4 at c.2091, which is far beyond the MSH6 BP7 boundary requirement of -21/+7 from the splice junctions. This supports BP7.	cspec
PP2	N/A	PP2 is not used in the MSH6 VCEP framework.	cspec
BP3	N/A	BP3 is not used in the MSH6 VCEP framework.	cspec
BP1	N/A	BP1 is not used in the MSH6 VCEP framework.	cspec
BS3	Not assessed	No variant-specific RNA study with nonsense-mediated decay inhibition and no calibrated functional assay demonstrating no damaging effect were identified, so BS3 cannot be applied.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart
PM2	Met	This variant is absent from gnomAD v4.1, which is below the MSH6 PM2_Supporting threshold of less than 0.00002 (less than 1 in 50,000 alleles).	gnomad_v4 cspec
BP4	Met	For this synonymous variant, SpliceAI predicts no meaningful splicing impact with a maximum delta score of 0.02, which is below the MSH6 BP4 threshold of 0.1 or less. This supports BP4.	spliceai cspec
PS1	Not assessed	No evidence was identified that this variant affects the same non-canonical splice nucleotide as a previously established pathogenic or likely pathogenic splice variant with similar or worse predicted splicing impact, so PS1 was not assessed.	cspec spliceai
PS2	Not assessed	No confirmed or assumed de novo data were identified, so PS2 cannot be assessed.	cspec
BP5	Not assessed	No tumor evidence showing a pattern inconsistent with MSH6-related mismatch repair deficiency and no alternate molecular explanation meeting the MSH6 BP5 thresholds were identified.	cspec
PVS1	Not met	This variant is a synonymous substitution, p.(Asp697=), and does not fall into the MSH6 PVS1 categories for nonsense, frameshift, canonical +/-1 or 2 splice, initiation codon, or proven loss-of-function splicing variants. No RNA evidence showing a splice aberration from the variant allele was identified.	cspec pvs1_gene_context pvs1_variant_assessment
PP5	N/A	PP5 is not used in the MSH6 VCEP framework.	cspec
BP2	N/A	BP2 is not used in the MSH6 VCEP framework.	cspec
PS4	N/A	PS4 is not used in the MSH6 VCEP framework.	cspec
PM4	N/A	PM4 is not used in the MSH6 VCEP framework.	cspec
PS3	Not assessed	No calibrated damaging functional assay and no variant-specific RNA evidence demonstrating an abnormal splicing effect were identified, so PS3 cannot be applied.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart
PP3	Not met	This variant is not a missense substitution, so the MSH6 HCI-prior missense thresholds do not apply. SpliceAI predicts no splice defect, with a maximum delta score of 0.02, which is below the MSH6 PP3 splicing threshold of 0.2 or greater.	spliceai cspec
PM6	N/A	PM6 is not used in the MSH6 VCEP framework.	cspec
PM1	N/A	PM1 is not used in the MSH6 VCEP framework because no recognized mutational hot spot is used for classification purposes in these mismatch repair genes.	cspec
PM3	Not assessed	No evidence was identified for co-occurrence with another pathogenic or likely pathogenic MSH6 variant in a context meeting the CMMRD-based PM3 scoring framework.	cspec vcep_table_for_cmmrd_diagnosis
BS4	Not assessed	No family data showing lack of segregation with disease were identified, so BS4 cannot be assessed.	cspec
PM5	Not assessed	This is not a missense change, and no qualifying pathogenic or likely pathogenic missense comparator at the same residue was identified for PM5 assessment.	cspec

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