LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-09-30
Case ID: NM_000179.3_c.1019T_C_20260930_211634
Framework: ACMG/AMP 2015
Variant classification summary

NM_000179.3:c.1019T>C

MSH6  · NP_000170.1:p.(Phe340Ser)  · NM_000179.3
GRCh37: chr2:48026141 T>C  ·  GRCh38: chr2:47799002 T>C
Gene: MSH6 Transcript: NM_000179.3
Final call
Likely Benign
BP4 supporting BP6 supporting benign
All criteria require review: For research and educational purposes only.
Variant details
Gene
MSH6
Transcript
NM_000179.3
Protein
NP_000170.1:p.(Phe340Ser)
gnomAD AF
9.10721985696089e-05 (v4.1)
ClinVar
Likely benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Likely Benign: BP4 supporting reflects an MSH6 HCI prior probability of 0.0019, below the VCEP cutoff.
2
Likely Benign: BP6 supporting benign reflects the exact-variant InSiGHT expert-panel Likely benign classification.
Final determination: InSiGHT MSH6 Version 2.0 Rule19 classifies a variant as Likely Benign when at least two benign supporting criteria are met; BP4 and BP6 are both adjudicated at supporting strength here.
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: NM_000179.3:c.1019T>C is a missense SNV producing p.Phe340Ser, not a qualifying null or canonical splice variant.
cspec
PS1 Not met Not met: no different nucleotide change producing the same p.Phe340Ser substitution was established as Pathogenic by the MSH6 VCEP.
cspec clinvar PMID:10699937 PMID:22290698 PMID:22949379 PMID:23621914
PS2 Not assessed Not assessed: no confirmed de novo observation or parental testing is documented for MSH6 c.1019T>C.
cspec
PS3 Not assessed Not assessed: p.Phe340Ser lacks calibrated functional odds or a documented validated assay sufficient to meet the MSH6 VCEP PS3 thresholds of 2.08, 4.3, and 18.7.
cspec PMID:22949379
PS4 N/A Not applicable: the MSH6 VCEP excludes PS4 proband counting when tumor IHC evidence is available.
cspec
PM1 N/A Not applicable: the governing MSH6 VCEP explicitly designates PM1 as Not Applicable.
cspec vcep_mmr_functional_domains
PM2 Not met Not met: gnomAD v4.1 allele frequency 9.10722e-05 exceeds the MSH6 VCEP PM2 cutoff of <0.00002.
cspec gnomad_v4 PMID:10699937
PM3 Not assessed Not assessed: no qualifying affected-proband observation with a pathogenic MSH6 variant confirmed in trans and no PM3 point count is documented.
cspec PMID:10699937
PM4 N/A Not applicable: p.Phe340Ser is a missense substitution with no protein-length change, and the MSH6 VCEP does not use PM4 for in-frame length changes.
cspec
PM5 Not assessed Not assessed: no qualifying alternate missense change at residue 340 was identified for comparison under the MSH6 PM5 rule.
cspec pm5_candidates PMID:10699937 PMID:22290698 PMID:22949379 PMID:23621914
PM6 N/A Not applicable: the MSH6 VCEP explicitly excludes PM6 from use for this gene.
cspec
PP1 Not met Not met: the exact-variant segregation likelihood ratio was 1.000, below the MSH6 PP1 Supporting threshold of >2.08.
cspec PMID:22949379 PMID:10699937
PP2 N/A Not applicable: the governing MSH6 VCEP explicitly designates PP2 as Not Applicable.
cspec
PP3 Not met Not met: MSH6 HCI prior probability 0.0019 is below the VCEP PP3 supporting threshold of >0.68.
cspec vcep_hci_priors_msh6 revel
PP4 Not met Not met: the reported tumor had MSI at BAT40 only, not documented MSI-H by the VCEP-required standard panel or consistent MMR-protein loss.
cspec PMID:10699937
PP5 Not met Not met: the exact-variant ClinVar expert panel classified the variant Likely benign, not Pathogenic or Likely pathogenic.
clinvar
BA1 Not met Not met: gnomAD v4 Grpmax filtering allele frequency 9.857e-05 is below the MSH6 VCEP BA1 threshold of 0.0022.
cspec gnomad_v4
BS1 Not met Not met: gnomAD v4 Grpmax filtering allele frequency 9.857e-05 is below the MSH6 VCEP BS1 lower threshold of 0.00022.
cspec gnomad_v4
BS2 Not assessed Not assessed: no qualifying in-trans co-occurrence, phase confirmation, and CMMRD exclusion are documented for the BS2 rule.
cspec
BS3 Not assessed Not assessed: the reported p.Phe340Ser "Wild type" result lacks calibrated functional odds and documented concordant protein and mRNA assay evidence required for MSH6 BS3.
cspec PMID:22949379
BS4 Not met Not met: the segregation likelihood ratio was 1.000, above the MSH6 BS4 Supporting range of >0.05 to ≤0.48.
cspec PMID:22949379 PMID:10699937
BP1 N/A Not applicable: the governing MSH6 VCEP explicitly designates BP1 as Not Applicable.
cspec
BP2 N/A Not applicable: the governing InSiGHT MSH6 Version 2.0 specification explicitly designates BP2 as not applicable.
cspec
BP3 N/A Not applicable: the variant is a missense SNV, not an in-frame insertion or deletion in a repetitive region.
cspec
BP4 Met Met, supporting: MSH6 HCI prior probability 0.0019 is below the VCEP BP4 threshold of <0.11.
cspec vcep_hci_priors_msh6
BP5 Not met Not met: one tumor showed MSI at BAT40 only with positive MSH6 staining, without the VCEP-required qualifying tumor count or alternate molecular basis.
cspec PMID:10699937
BP6 Met Met, supporting: the exact-variant ClinVar expert panel classified NM_000179.3:c.1019T>C as Likely benign with three-star review.
clinvar
BP7 N/A Not applicable: c.1019T>C is an exonic missense variant, whereas BP7 applies only to synonymous or qualifying intronic variants.
cspec
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