Variant classification summary

NM_000249.4:c.1897-7C>T

MLH1 · NP_000240.1:p.? · NM_000249.4

GRCh37: chr3:37090001 C>T · GRCh38: chr3:37048510 C>T

Gene: MLH1 Transcript: NM_000249.4

Final call

VUS

BP4 supporting

Variant details

Gene

MLH1

Transcript

NM_000249.4

Protein

NP_000240.1:p.?

gnomAD AF

2.3610403489369106e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: BP4 supporting is met because SpliceAI's maximum delta score is 0.099, at or below the VCEP no-impact cutoff of 0.1.

Final determination: Under the MLH1 VCEP Version 2.0 framework, at least two benign supporting criteria are required for Likely Benign; the single applied BP4 supporting criterion therefore leaves the variant as 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.1897-7C>T is a non-canonical intronic variant outside the VCEP's named PVS1 classes, with no RNA evidence of a loss-of-function splice consequence.	cspec pvs1_variant_assessment vcep_pvs1_decisiontree_mmr
PS1	Not assessed	Not assessed: PS1 requires a qualifying pathogenic same-amino-acid or same-nucleotide splice comparator, but none was identified for c.1897-7C>T.	cspec vcep_mmr_functional_domains
PS2	Not assessed	Not assessed: no documented de novo result, parental confirmation, qualifying tumor findings, or VCEP de novo point total is available.	cspec
PS3	Not assessed	Not assessed: no variant-specific calibrated functional odds, MMR assay readout, or patient RNA expression result is available for c.1897-7C>T.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart
PS4	N/A	Not applicable: the MLH1 VCEP excludes PS4 from MMR classification because tumor IHC evidence is handled through PP4 rather than proband counting.	cspec
PM1	N/A	Not applicable: the MLH1 VCEP explicitly marks PM1 not applicable, and its authoritative domain_tables entry is empty.	cspec vcep_mmr_functional_domains
PM2	Not met	Not met: gnomAD v4.1 total AF is 2.36104e-05, exceeding the VCEP PM2 cutoff of <0.00002.	cspec gnomad_v4 vcep_vcep_pilot_variants_mmr
PM3	Not assessed	Not assessed: no documented second pathogenic MLH1 allele or phase, and gnomAD v4.1 grpmax 0.00002081 exceeds the PM2 threshold of <0.00002.	cspec gnomad_v4
PM4	N/A	Not applicable: the MLH1 VCEP explicitly marks PM4 Not Applicable, and this variant has no defined protein-length change beyond p.?.	cspec
PM5	N/A	Not applicable: PM5 requires a missense change at a defined amino-acid residue, while c.1897-7C>T has protein consequence p.? .	cspec
PM6	N/A	Not applicable: the MLH1 VCEP marks PM6 Not Applicable and directs de novo assessment to PS2.	cspec
PP1	Not assessed	Not assessed: no pedigree segregation data, informative meioses, family count, or combined Bayes Likelihood Ratio is available.	cspec
PP2	N/A	Not applicable: the MLH1 VCEP explicitly marks PP2 not applicable for this specification.	cspec
PP3	Not met	Not met: SpliceAI maximum delta score 0.099 is below the VCEP PP3 threshold of 0.2 for a predicted non-canonical splice defect.	cspec spliceai
PP4	Not assessed	Not assessed: no patient-specific MSI-H tumor, MLH1-consistent protein loss, or promoter-methylation exclusion is available to satisfy the PP4 supporting rule.	cspec vcep_table_for_cmmrd_diagnosis vcep_vcep_pilot_variants_mmr
PP5	N/A	Not applicable: the MLH1 VCEP prohibits PP5 regardless of the available external classifications or literature.	cspec
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 2.081e-05, below the VCEP BA1 threshold of 0.001 (0.1%).	cspec gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 2.081e-05, below the VCEP BS1 lower threshold of 0.0001.	cspec gnomad_v4
BS2	Not assessed	Not assessed: no confirmed in-trans co-occurrence, phase, cancer-age, or CMMRD information is available for BS2.	cspec
BS3	Not assessed	Not assessed: no variant-specific calibrated odds or NMD-inhibited protein/mRNA assay result demonstrates proficient function for c.1897-7C>T.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart
BS4	Not assessed	Not assessed: no non-segregation pedigree data, informative meioses, or combined Bayes Likelihood Ratio is available.	cspec
BP1	N/A	Not applicable: the MLH1 VCEP explicitly marks BP1 not applicable for this specification.	cspec
BP2	N/A	Not applicable: the MLH1 VCEP explicitly marks BP2 as not applicable.	cspec
BP3	N/A	Not applicable: the MLH1 VCEP explicitly marks BP3 Not Applicable for this framework.	cspec
BP4	Met	Met at Supporting: SpliceAI maximum delta score 0.099 meets the VCEP BP4 no-impact cutoff of <=0.1 for intronic variants.	cspec spliceai
BP5	Not assessed	Not assessed: no patient-specific MSS, absent or inconsistent MMR-protein loss, BRAF V600E, or MLH1-methylation tumor evidence is available.	cspec vcep_vcep_pilot_variants_mmr
BP6	N/A	Not applicable: the MLH1 VCEP prohibits BP6 regardless of the available external benign classifications or literature.	cspec
BP7	N/A	Not applicable: c.1897-7C>T lies 7 bases upstream of the exon, not at or beyond the VCEP BP7 boundary of -21/+7.	cspec

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