Variant classification summary

NM_000249.4:c.342_347del

MLH1 · NP_000240.1:p.(Ile115_Thr116del) · NM_000249.4

GRCh37: chr3:37045922 GTTACTA>G · GRCh38: chr3:37004431 GTTACTA>G

Gene: MLH1 Transcript: NM_000249.4

Final call

VUS

PM2 supporting

Variant details

Gene

MLH1

Transcript

NM_000249.4

Protein

NP_000240.1:p.(Ile115_Thr116del)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000249.4:c.342_347del (p.Ile115_Thr116del) is an in-frame deletion in exon 4 of MLH1. It is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada), meeting PM2_Supporting under the InSiGHT MLH1 VCEP framework.

2

Under the InSiGHT MLH1 VCEP v2.0.0, PVS1 is not applicable because this in-frame deletion does not introduce a premature termination codon and does not meet the VCEP criteria for nonsense, frameshift, or canonical splice variants.

3

No functional studies, tumor phenotype data, segregation data, or de novo observations were identified for this variant in any reviewed publication or database. Six papers were reviewed in full text; none mention NM_000249.4:c.342_347del.

4

This variant has been reported in ClinVar as Uncertain Significance (1 clinical laboratory, criteria provided, single submitter). Under the InSiGHT MLH1 VCEP framework, PP5 is not applicable and this single submission does not constitute independent evidence for classification.

5

With PM2_Supporting as the only met criterion and no benign criteria met, this variant remains a Variant of Uncertain Significance under the InSiGHT MLH1 VCEP classification rules. All other applicable criteria are either not met, not applicable by VCEP designation, or cannot be assessed due to absence of data.

Final determination: No criteria-combination rule matched the adjudicated criteria in the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MLH1 Version 2.0.0 v2.0.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

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	NM_000249.4:c.342_347del is an in-frame deletion of 6 nucleotides removing Ile115 and Thr116 (p.Ile115_Thr116del). It does not introduce a premature termination codon and is not a canonical splice variant; therefore it does not satisfy the InSiGHT MLH1 VCEP PVS1 criteria, which require nonsense, frameshift, or canonical splice variants introducing a PTC at or before codon 753.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	N/A	InSiGHT MLH1 VCEP PS1 applies only to missense substitutions encoding the same amino acid change or splice variants affecting the same non-canonical splice nucleotide; this in-frame deletion does not qualify.	cspec
PS2	Not assessed	No de novo observation data have been reported for NM_000249.4:c.342_347del in the available evidence.
PS3	Not assessed	No variant-specific functional studies or calibrated functional assay data were identified for NM_000249.4:c.342_347del in the literature or InSiGHT VCEP functional assay documentation.	vcep_functional_assay_svi_documentation_mmr
PS4	N/A	InSiGHT MLH1 VCEP PS4 is designated Not Applicable for this VCEP.	cspec
PS5	N/A	PS5 is not included in the InSiGHT MLH1 VCEP criteria; its supporting-strength counterpart PP5 is also explicitly designated Not Applicable by this VCEP.	cspec
PM1	N/A	InSiGHT MLH1 VCEP PM1 is designated Not Applicable for this VCEP.	cspec
PM2	Met	NM_000249.4:c.342_347del is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, meeting the InSiGHT MLH1 VCEP PM2_Supporting threshold (allele frequency <0.00002 in gnomAD v4).	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM4	N/A	InSiGHT MLH1 VCEP PM4 is designated Not Applicable for this VCEP.	cspec
PM5	N/A	InSiGHT MLH1 VCEP PM5 applies only to missense changes at an amino acid residue where a different missense change was classified as Pathogenic or Likely Pathogenic; this variant is an in-frame deletion, not a missense substitution.	cspec pm5_candidates
PM6	N/A	InSiGHT MLH1 VCEP PM6 is designated Not Applicable for this VCEP.	cspec
PP1	Not assessed	No co-segregation data are available for NM_000249.4:c.342_347del in any reported pedigrees.
PP2	N/A	InSiGHT MLH1 VCEP PP2 is designated Not Applicable for this VCEP.	cspec
PP3	N/A	InSiGHT MLH1 VCEP PP3 applies only to missense variants with HCI prior scores or splice predictions for non-canonical splice sites. This is an in-frame coding deletion with no HCI prior available and a SpliceAI max delta score of 0.00; neither PP3 rule applies.	cspec spliceai
PP4	Not assessed	No tumor MSI or MMR immunohistochemistry data have been reported for patients carrying NM_000249.4:c.342_347del.
PP5	N/A	InSiGHT MLH1 VCEP PP5 is designated Not Applicable for this VCEP.	cspec
BA1	Not met	NM_000249.4:c.342_347del is absent from gnomAD v4.1; the InSiGHT MLH1 VCEP BA1 threshold requires a gnomAD v4 Grpmax filtering allele frequency >= 0.001 (0.1%), which is not met.	gnomad_v4 cspec
BS1	Not met	NM_000249.4:c.342_347del is absent from gnomAD v4.1; the InSiGHT MLH1 VCEP BS1 threshold requires a gnomAD v4 Grpmax filtering allele frequency >= 0.0001 (0.01%), which is not met.	gnomad_v4 cspec
BS2	Not assessed	No data are available regarding co-occurrence in trans with a known pathogenic MLH1 variant in a patient with colorectal or Lynch syndrome spectrum cancer after age 45 without CMMRD features.
BS3	Not assessed	No variant-specific functional studies demonstrating normal MMR function have been identified for NM_000249.4:c.342_347del in the literature or InSiGHT VCEP calibrated functional assay documentation.	vcep_functional_assay_svi_documentation_mmr
BS4	Not assessed	No segregation data are available to evaluate lack of co-segregation with disease for NM_000249.4:c.342_347del.
BP1	N/A	InSiGHT MLH1 VCEP BP1 is designated Not Applicable for this VCEP.	cspec
BP2	N/A	InSiGHT MLH1 VCEP BP2 is designated Not Applicable for this VCEP.	cspec
BP3	N/A	InSiGHT MLH1 VCEP BP3 is designated Not Applicable for this VCEP.	cspec
BP4	N/A	InSiGHT MLH1 VCEP BP4 applies only to missense variants with HCI prior <0.11 or intronic/synonymous variants with SpliceAI delta <= 0.1. This is an in-frame coding deletion; neither BP4 rule applies.	cspec spliceai
BP5	Not assessed	No tumor phenotype data (MSS status, MMR IHC, BRAF V600E, or MLH1 promoter methylation) are available for patients carrying NM_000249.4:c.342_347del.
BP6	N/A	InSiGHT MLH1 VCEP BP6 is designated Not Applicable for this VCEP.	cspec
BP7	N/A	InSiGHT MLH1 VCEP BP7 applies only to synonymous or intronic variants at or beyond -21/+7; this is an in-frame coding deletion and does not qualify.	cspec

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