NM_000179.3:c.866G>A

MSH6 · NP_000170.1:p.(Gly289Asp) · NM_000179.3

GRCh37: chr2:48025988 G>A · GRCh38: chr2:47798849 G>A

Gene: MSH6 Transcript: NM_000179.3

Final call

Likely Benign

BS1 strong BP4 supporting

Variant details

Gene

MSH6

Transcript

NM_000179.3

Protein

NP_000170.1:p.(Gly289Asp)

gnomAD AF

0.0002168455539226741 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The MSH6 c.866G>A (p.Gly289Asp; p.G289D) variant has not been observed in COSMIC and has been reported in ClinVar with conflicting germline classifications, including uncertain significance, likely benign, and benign submissions.

This variant is present in gnomAD v4.1 at an allele frequency of 0.000216846 (350/1614052 alleles) with grpmax filtering allele frequency 0.00024593, which exceeds the MSH6 BS1 threshold of 0.00022 but remains below the BA1 threshold of 0.0022.

Computational data support a benign interpretation: the MSH6 HCI prior probability is 0.0021, below the BP4 threshold of 0.11, SpliceAI predicts no significant splice impact with a max delta score of 0.01, and additional predictors are not strongly damaging (REVEL 0.272; BayesDel -0.256015).

Final determination: Rule18 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	Population frequency does not meet the MSH6 BA1 threshold. In gnomAD v4.1, the grpmax filtering allele frequency is 0.00024593, which is below the BA1 threshold of 0.0022 (0.22%).	gnomad_v4 cspec
BS2	Not assessed	No confirmed observation of this variant in trans with a known pathogenic MSH6 variant in an individual meeting the MSH6 BS2 requirements was identified.	cspec
BP6	N/A	This criterion is not used in the MSH6 VCEP framework.	cspec
PP4	Not assessed	No tumor MSI or mismatch repair immunohistochemistry findings were identified to support the MSH6 PP4 phenotype-specific rule.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be applied.	cspec
BS1	Met	Population frequency meets the MSH6 BS1 threshold. In gnomAD v4.1, the grpmax filtering allele frequency is 0.00024593, which is above the BS1 threshold of 0.00022 and below the BA1 threshold of 0.0022.	gnomad_v4 cspec
BP7	N/A	This is a missense variant, not a synonymous or qualifying intronic variant, so BP7 does not apply.	cspec
PP2	N/A	This criterion is not used in the MSH6 VCEP framework.	cspec
BP3	N/A	This criterion is not used in the MSH6 VCEP framework.	cspec
BP1	N/A	This criterion is not used in the MSH6 VCEP framework.	cspec
BS3	Not assessed	No calibrated functional assay result or variant-specific protein and RNA assay result meeting the MSH6 BS3 requirements was identified.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart
PM2	Not met	Population frequency is too high for PM2. In gnomAD v4.1, the allele frequency is 0.000216846 (350/1614052 alleles), which is above the MSH6 PM2 threshold of <0.00002.	gnomad_v4 cspec
BP4	Met	Computational evidence supports a benign interpretation. For this MSH6 missense variant, the HCI prior probability is 0.0021, which is below the BP4 threshold of 0.11. Additional predictors do not suggest a damaging effect, with REVEL 0.272, BayesDel -0.256015, and SpliceAI max delta 0.01 indicating no significant splice impact.	hci_prior revel bayesdel spliceai cspec
PS1	Not assessed	No previously established pathogenic or likely pathogenic variant causing the same amino acid change by a different nucleotide change was identified in the reviewed materials.	cspec clinvar
PS2	Not assessed	No confirmed de novo data were identified for this variant.	cspec
BP5	Not assessed	No tumor data were identified showing mismatch repair findings inconsistent with MSH6 involvement, so BP5 cannot be applied.	cspec
PVS1	Not met	This variant is a missense substitution, p.(Gly289Asp), and does not fall into the MSH6 PVS1 null-variant categories. The reviewed PVS1 assessments indicate that it is not a nonsense, frameshift, canonical ±1/2 splice, initiation codon, or proven splice-aberrant loss-of-function variant.	cspec pvs1_gene_context pvs1_variant_assessment
PP5	N/A	This criterion is not used in the MSH6 VCEP framework.	cspec
BP2	N/A	This criterion is not used in the MSH6 VCEP framework.	cspec
PS4	N/A	This criterion is not used in the MSH6 VCEP framework.	cspec
PM4	N/A	This criterion is not used in the MSH6 VCEP framework.	cspec
PS3	Not assessed	No calibrated functional assay result or variant-specific mismatch repair defect meeting the MSH6 PS3 requirements was identified in the reviewed materials.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart
PP3	Not met	Computational evidence does not support pathogenicity under the MSH6 missense PP3 rule. The HCI prior probability is 0.0021, which is below the PP3 thresholds of >0.68 for supporting and >0.81 for moderate evidence. SpliceAI also does not predict a splice defect, with a max delta score of 0.01, below the non-canonical splice threshold of 0.2.	hci_prior spliceai cspec
PM6	N/A	This criterion is not used in the MSH6 VCEP framework.	cspec
PM1	N/A	This criterion is not used in the MSH6 VCEP framework.	cspec hotspots
PM3	Not assessed	No qualifying in trans observations in the recessive/CMMRD framework were identified for this variant.	cspec
BS4	Not assessed	No lack-of-segregation data were identified for this variant, so BS4 cannot be applied.	cspec
PM5	Not assessed	The MSH6 framework uses classic same-residue PM5 logic for missense variants, but no verified same-residue pathogenic or likely pathogenic comparator variant for codon 289 was identified in the reviewed materials. PM5 therefore cannot be applied at this time.	pm5_candidates cspec

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