Variant classification summary

NM_000179.3:c.1301A>G

MSH6 · NP_000170.1:p.(Glu434Gly) · NM_000179.3

GRCh37: chr2:48026423 A>G · GRCh38: chr2:47799284 A>G

Gene: MSH6 Transcript: NM_000179.3

Final call

VUS

PM2 supporting PP3 moderate

Variant details

Gene

MSH6

Transcript

NM_000179.3

Protein

NP_000170.1:p.(Glu434Gly)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 Supporting: the variant is absent from gnomAD v4.1.

2

PP3 Moderate: the MSH6 HCI prior pathogenicity probability is 0.9328, above the 0.81 threshold.

Final determination: Under the MSH6 VCEP criteria-combination rules, PM2 Supporting plus PP3 Moderate satisfy no pathogenic or benign rule, so the classification is VUS.

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
PVS1	N/A	Not applicable: c.1301A>G is a missense substitution, not a VCEP-specified nonsense, frameshift, splice-site, genomic-alteration, or qualifying RNA-aberration variant.	cspec vcep_pvs1_decisiontree_mmr vcep_vcep_pilot_variants_mmr
PS1	Not assessed	Not assessed: no VCEP-established pathogenic variant with a different nucleotide change encoding the same p.Glu434Gly amino-acid change was available.	cspec
PS2	Not assessed	Not assessed: no proband, parental-testing, de novo, tumor, or de novo-point data are available to apply the VCEP PS2 rule.
PS3	Not assessed	Not assessed: no variant-specific functional assay result or calibrated functional odds were available for c.1301A>G in the governing functional-assay sources.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart
PS4	N/A	Not applicable: the MSH6 VCEP specification explicitly marks PS4 as Not Applicable.	cspec
PM1	N/A	Not applicable: the MSH6 VCEP marks PM1 Not Applicable, regardless of p.E434G's location in the functional-domain schematic.	cspec vcep_mmr_functional_domains
PM2	Met	Met at Supporting: gnomAD v4.1 reports the variant absent, satisfying the VCEP PM2 threshold of <0.00002 allele frequency.	cspec gnomad_v4
PM3	Not assessed	Not assessed: no documented pathogenic partner variant, affected-proband CMMRD features, or phase evidence is available to assign PM3 points.	cspec
PM4	N/A	Not applicable: the MSH6 VCEP specification explicitly marks PM4 Not Applicable.	cspec
PM5	Not met	Not met: the comparator search found 0 same-residue variants at Glu434, including 0 expert-panel Pathogenic/Likely Pathogenic candidates.	cspec pm5_candidates
PM6	N/A	Not applicable: the MSH6 VCEP explicitly marks PM6 as not applicable for this specification.	cspec
PP1	Not assessed	Not assessed: no pedigree segregation results or combined Bayes Likelihood Ratio are available for comparison with the VCEP thresholds.
PP2	N/A	Not applicable: the MSH6 VCEP explicitly marks PP2 Not Applicable for this framework.	cspec
PP3	Met	Met at moderate strength: HCI prior pathogenicity probability is 0.9328, exceeding the VCEP PP3_Moderate threshold of >0.81.	vcep_hci_priors_msh6
PP4	Not assessed	Not assessed: no patient tumor phenotype, MSI, tumor-genome, or MMR-protein-expression evidence is available for the PP4 rule.	cspec vcep_table_for_cmmrd_diagnosis vcep_vcep_pilot_variants_mmr
PP5	N/A	Not applicable: the MSH6 VCEP specification explicitly marks PP5 as Not Applicable.	cspec
BA1	Not met	Not met: gnomAD v4.1 reports the variant absent, providing no Grpmax allele frequency ≥0.0022 (0.22%) required for BA1.	cspec gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 reports the variant absent, not within the BS1 Grpmax allele-frequency interval of 0.00022 to <0.0022.	cspec gnomad_v4
BS2	Not assessed	Not assessed: no documented in-trans co-occurrence, qualifying patient age, CMMRD assessment, or parental/offspring phase confirmation is available.	cspec
BS3	Not assessed	Not assessed: no variant-specific proficient-function assay result or calibrated functional odds were available for c.1301A>G in the governing functional-assay sources.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart
BS4	Not assessed	Not assessed: no non-segregation pedigree data or combined Bayes Likelihood Ratio are available for comparison with the VCEP thresholds.
BP1	N/A	Not applicable: the MSH6 VCEP explicitly marks BP1 Not Applicable for this framework.	cspec
BP2	N/A	Not applicable: the MSH6 VCEP explicitly excludes BP2 and directs evaluators to use BS2 instead.	cspec
BP3	N/A	Not applicable: the MSH6 VCEP specification explicitly marks BP3 Not Applicable.	cspec
BP4	Not met	Not met: HCI prior pathogenicity probability is 0.9328, not below the VCEP BP4 missense threshold of <0.11.	vcep_hci_priors_msh6
BP5	Not assessed	Not assessed: no tumor MSS, MMR-protein, BRAF V600E, or MLH1-methylation evidence is available for BP5.	cspec
BP6	N/A	Not applicable: the MSH6 VCEP specification explicitly marks BP6 as Not Applicable.	cspec
BP7	N/A	Not applicable: the variant is missense, whereas the VCEP BP7 rule covers only synonymous or intronic variants at or beyond -21/+7.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.