LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-08-01
Case ID: NM_000179.2_c.1796G_A_20260801_013307
Framework: ACMG/AMP 2015
Variant classification summary

MSH6  · NP_000170.1:p.(Gly599Glu)  · NM_000179.2
GRCh37: chr2:48026918 G>A  ·  GRCh38: chr2:47799779 G>A
Gene: MSH6 Transcript: NM_000179.2
Final call
All criteria require review: For research and educational purposes only.
Variant details
Gene
MSH6
Transcript
NM_000179.2
Protein
NP_000170.1:p.(Gly599Glu)
gnomAD AF
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
The variant NM_000179.2:c.1796G>A (p.Gly599Glu) in MSH6 is a missense substitution absent from all gnomAD population databases (PM2_Supporting).
2
In silico prediction supports a deleterious effect: HCI prior probability for pathogenicity is 0.9346, meeting the MSH6 VCEP threshold for PP3_Moderate (>0.81). REVEL score is 0.807, also consistent with a damaging prediction.
3
No functional assay data, segregation data, or tumor phenotype data are available for this variant. The variant has not been reported in ClinVar with expert panel review (currently Uncertain significance, 1-star).
4
Multiple VCEP criteria are marked Not Applicable (PP5, BP6, PM1, PP2, PS4, PM6, BP1, BP2) as per the InSiGHT MSH6 VCEP v2.0 framework.
Final determination:
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 PVS1 is not applicable to missense variants. c.1796G>A (p.Gly599Glu) is a missense substitution and does not fall into any PVS1 null-variant category (nonsense, frameshift, canonical splice ±1,2, initiation codon) under the InSiGHT MSH6 VCEP v2.0.
cspec
PS1 Not met No different nucleotide change encoding the same amino acid substitution (Gly599Glu) has been previously classified as Pathogenic or Likely Pathogenic by this VCEP.
cspec
PS2 Not met No de novo occurrence data are available for this variant. The InSiGHT MSH6 VCEP requires de novo points from confirmed parentage testing.
cspec
PS3 Not met No variant-specific functional assay data or calibrated functional odds for pathogenicity are available for c.1796G>A (p.Gly599Glu). The variant was not listed in the VCEP MMR functional assay SVI documentation spreadsheet, and no independent functional studies were identified in the literature.
cspec vcep_functional_assay_svi_documentation_mmr
PS4 N/A PS4 is marked Not Applicable in the InSiGHT MSH6 VCEP v2.0 criteria.
cspec
PS5 N/A PS5 is not defined in the InSiGHT MSH6 VCEP v2.0 criteria set. This VCEP does not use PS5.
cspec
PM1 N/A PM1 is marked Not Applicable in the InSiGHT MSH6 VCEP v2.0 criteria.
cspec
PM2 Met This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the InSiGHT MSH6 VCEP threshold for PM2_Supporting (allele frequency < 0.00002, i.e., <1 in 50,000 alleles).
gnomad_v2 gnomad_v4 gnomad_canada cspec
PM5 Not met No different missense change at amino acid residue Gly599 has been classified as Pathogenic or Likely Pathogenic by the InSiGHT MSH6 VCEP. The PM5 candidate search identified zero comparator variants at this residue.
cspec pm5_candidates
PM6 N/A PM6 is marked Not Applicable in the InSiGHT MSH6 VCEP v2.0 criteria.
cspec
PP1 Not met No co-segregation data with Bayes likelihood ratios are available for this variant.
cspec
PP2 N/A PP2 is marked Not Applicable in the InSiGHT MSH6 VCEP v2.0 criteria.
cspec
PP3 Met The HCI prior probability for pathogenicity is 0.9346, which exceeds the InSiGHT MSH6 VCEP threshold of >0.81 for PP3_Moderate in missense variants.
hci_prior cspec
PP4 Not met No MSI-H tumor data or MMR protein immunohistochemistry results are available for this variant. The InSiGHT MSH6 VCEP requires MSI-H status or loss of MMR protein expression consistent with the variant location.
cspec
PP5 N/A PP5 is marked Not Applicable in the InSiGHT MSH6 VCEP v2.0 criteria. The ClinVar record (VariationID 2693765) has 1-star review status (criteria provided, single submitter), which does not trigger the PP5 global override threshold (requires 3-star expert panel).
cspec
BA1 Not met The variant is absent from all gnomAD population databases. The InSiGHT MSH6 VCEP BA1 threshold requires gnomAD v4 Grpmax filtering allele frequency ≥ 0.0022 (0.22%), which is not met.
gnomad_v2 gnomad_v4 cspec
BS1 Not met The variant is absent from all gnomAD population databases. The InSiGHT MSH6 VCEP BS1 threshold requires gnomAD v4 Grpmax filtering allele frequency ≥ 0.00022 (0.022%) and < 0.0022, which is not met.
gnomad_v2 gnomad_v4 cspec
BS2 Not met No evidence of co-occurrence in trans with a known pathogenic MSH6 variant in a patient with colorectal cancer after age 45 without clinical manifestations of CMMRD.
cspec
BS3 Not met No calibrated functional assay data with functional odds for pathogenicity ≤ 0.05 (BS3_Strong) or ≤ 0.48 (BS3_Supporting) are available for this variant. No variant-specific proficient function has been demonstrated in protein or mRNA-based laboratory assays per the MMR functional assay flowchart.
cspec vcep_functional_assay_svi_documentation_mmr
BS4 Not met No co-segregation data are available to evaluate lack of co-segregation with disease.
cspec
BP1 N/A BP1 is marked Not Applicable in the InSiGHT MSH6 VCEP v2.0 criteria.
cspec
BP2 N/A BP2 is marked Not Applicable in the InSiGHT MSH6 VCEP v2.0 criteria.
cspec
BP3 N/A BP3 applies to in-frame deletions/insertions in repetitive regions; not applicable to this missense substitution.
BP4 Not met The HCI prior probability for pathogenicity is 0.9346, which substantially exceeds the InSiGHT MSH6 VCEP BP4_Supporting threshold of < 0.11. In silico predictions are consistent with a deleterious effect, not a benign one.
hci_prior cspec
BP5 Not met No tumor data (MSS status, MMR IHC, BRAF V600E mutation, MLH1 methylation) are available for this variant to support a benign interpretation.
cspec
BP6 N/A BP6 is Not Applicable for this VCEP as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
cspec
BP7 N/A BP7 applies only to synonymous (silent) or intronic variants at or beyond position -21/+7. c.1796G>A is a missense substitution and does not meet this criterion.
cspec
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.