LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-13
Case ID: NM_002439.5_c.1897-12T_A_20261013_161212
Framework: ACMG/AMP 2015
Variant classification summary

NM_002439.5:c.1897-12T>A

MSH3  · NP_002430.3:p.?  · NM_002439.5
GRCh37: chr5:80063740 T>A  ·  GRCh38: chr5:80767921 T>A
Gene: MSH3 Transcript: NM_002439.5
Final call
VUS
All criteria require review: For research and educational purposes only.
Variant details
Gene
MSH3
Transcript
NM_002439.5
Protein
NP_002430.3:p.?
gnomAD AF
0.00033546003133501655 (v4.1)
ClinVar
Uncertain significance
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Only PVS1, PM4, and BP3 were adjudicated. No applicable MSH3 VCEP or gene-specific framework was available; the generic ClinGen SVI PVS1 framework was used for the consequence assessment.
2
No applicable MSH3-specific VCEP or gene-specific functional-evidence specification was identified, so generic ACMG/AMP principles were used.
3
No validated variant-specific functional assay with interpretable abnormal or normal results was found; computational SpliceAI output does not satisfy PS3 or BS3.
4
No applicable MSH3-specific VCEP or gene-specific computational-evidence specification was identified, so the supplied generic ACMG/ClinGen-SVI calibration thresholds were used.
5
The intronic consequence selects SpliceAI as the sole PP3/BP4 path; the SpliceAI maximum delta of 0.163 falls between the supplied PP3 supporting and BP4 supporting cutoffs.
6
BP7 is upstream not_applicable because the variant is not synonymous.
7
No applicable MSH3-specific VCEP or gene framework was available, so the supplied generic population thresholds were used.
8
BA1 and BS1 are not met because the observed frequencies remain below 0.05 and 0.01, respectively; PM2 is not met because all-comers and non-cancer frequencies exceed 0.0001.
9
BS2 remains not assessed because homozygote observations lack documented age, health status, inheritance-model context, and penetrance information.
Final determination: Under the generic ACMG/AMP 2015 fallback, the absence of any applied pathogenic or benign criteria satisfies none of the defined combination thresholds and therefore yields 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 Not met Not met: c.1897-12T>A is a noncanonical intronic SNV, and SpliceAI max delta 0.163 does not establish a loss-of-function splice consequence.
pvs1_generic_framework pvs1_variant_assessment spliceai
PS1 N/A Not applicable: the intronic variant has protein consequence p.? and therefore no defined amino-acid change for PS1 comparison.
PS2 Not assessed Not assessed: no documented affected proband with confirmed de novo status or parental genotyping is available.
PS3 Not assessed Not assessed: no validated variant-specific functional assay with interpretable abnormal results is available for NM_002439.5:c.1897-12T>A.
PS4 Not assessed Not assessed: no case-control enrichment, odds ratio, likelihood ratio, or affected-case excess is reported for the exact variant.
clinvar
PM1 N/A Not applicable: intronic c.1897-12T>A has protein consequence p.? and cannot be mapped to a critical functional residue or domain.
PM2 Not met Not met: gnomAD v4.1 overall AF is 0.00033546, exceeding the generic PM2 threshold of 0.0001.
gnomad_v2 gnomad_v4 PMID:25741868
PM3 Not assessed Not assessed: no affected proband, second pathogenic MSH3 variant, or confirmed trans phase is documented for NM_002439.5:c.1897-12T>A.
gnomad_v2 gnomad_v4 clinvar
PM4 N/A Not applicable: the intronic SNV has no defined amino-acid or protein-length change (NP_002430.3:p.?).
pvs1_variant_assessment
PM5 N/A Not applicable: protein consequence p.? provides no amino-acid residue for same-residue pathogenic alternate comparison under PM5.
PM6 Not assessed Not assessed: no affected-proband de novo observation is reported without parental testing.
PP1 Not assessed Not assessed: no informative meioses or affected-relative segregation data are reported for the variant.
PP2 N/A Not applicable: c.1897-12T>A is intronic with protein consequence p.?, not a missense variant eligible for PP2.
PP3 Not met Not met: SpliceAI maximum delta 0.163 is below the >=0.2 PP3 supporting threshold.
spliceai
PP4 Not assessed Not assessed: no patient phenotype or disease-specific clinical presentation is documented for this exact variant.
clinvar
PP5 Not met Not met: ClinVar lists 0 expert-panel submissions for the exact variant, so ordinary laboratory assertions cannot support PP5.
clinvar
BA1 Not met Not met: the highest observed allele frequency is 0.0061081, below the generic BA1 threshold of 0.05.
gnomad_v2 gnomad_v4 PMID:25741868
BS1 Not met Not met: the maximum supported subgroup frequency is 0.0061081, below the generic BS1 threshold of 0.01.
gnomad_v2 gnomad_v4 PMID:25741868
BS2 Not assessed Not assessed: three gnomAD v4.1 homozygotes are reported, but adult health, inheritance model, and penetrance are undocumented.
gnomad_v2 gnomad_v4 PMID:25741868
BS3 Not assessed Not assessed: no validated variant-specific functional assay with interpretable normal results is available for NM_002439.5:c.1897-12T>A.
BS4 Not assessed Not assessed: no phenotype-qualified unaffected relatives with negative variant testing are documented.
BP1 N/A Not applicable: the intronic variant has protein consequence p.? and is not an eligible missense variant for BP1.
BP2 Not assessed Not assessed: no relevant individual with a second pathogenic variant and documented cis or trans phase is reported for this variant.
clinvar gnomad_v2 gnomad_v4
BP3 N/A Not applicable: this is an intronic SNV, not an in-frame deletion or insertion in a repetitive region.
pvs1_variant_assessment
BP4 Not met Not met: SpliceAI maximum delta 0.163 exceeds the <=0.1 BP4 supporting threshold.
spliceai
BP5 Not assessed Not assessed: no affected individual has documented alternative molecular etiology explaining the phenotype alongside this variant.
clinvar
BP6 Not met Not met: ClinVar lists 0 expert-panel submissions, and ordinary laboratory Benign or Likely benign assertions cannot support BP6.
clinvar
BP7 N/A Not applicable: the variant is intronic, whereas BP7 applies only to synonymous variants.
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