Variant classification summary

NM_000249.4:c.1875T>G

MLH1 · NP_000240.1:p.(Tyr625Ter) · NM_000249.4

GRCh37: chr3:37089153 T>G · GRCh38: chr3:37047662 T>G

Gene: MLH1 Transcript: NM_000249.4

Final call

Pathogenic

PVS1 very strong PM2 supporting PP5 supporting

Variant details

Gene

MLH1

Transcript

NM_000249.4

Protein

NP_000240.1:p.(Tyr625Ter)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000249.4:c.1875T>G (p.Tyr625Ter) is a nonsense variant in MLH1 introducing a premature termination codon at position 625, upstream of the VCEP threshold at codon 753, meeting PVS1 at Very Strong strength.

2

The variant is absent from gnomAD v4.1, v2.1, and gnomAD-Canada, meeting PM2 at Supporting strength under the InSiGHT VCEP threshold of fewer than 1 in 50,000 alleles.

3

This variant has been classified as Pathogenic by the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) expert panel in ClinVar (ClinVar ID: 89914).

Final determination: Rule4 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 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Pathogenic.

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	Met	NM_000249.4:c.1875T>G is a nonsense variant introducing a premature termination codon at position 625 (p.Tyr625Ter), which is before codon 753 in MLH1, satisfying the InSiGHT VCEP v2.0.0 criterion for PVS1 at Very Strong strength.	gnomad_v4 gnomad_v2 cspec
PS1	N/A	PS1 per the InSiGHT VCEP applies to missense substitutions encoding the same amino acid change as a known pathogenic variant, or splice variants at the same non-canonical nucleotide. NM_000249.4:c.1875T>G is a nonsense variant.
PS2	Not met	No de novo observations are available for this variant. PS2 requires de novo occurrence data with confirmed parentage.
PS3	Not met	No variant-specific functional assay data were identified in the VCEP functional assay spreadsheet or the reviewed literature for NM_000249.4:c.1875T>G.
PS4	N/A	PS4 is marked Not Applicable by the InSiGHT MLH1 VCEP v2.0.0.
PS5	N/A	PS5 is not defined in the InSiGHT MLH1 VCEP v2.0.0 specification; PP5 (which addresses similar evidence) is explicitly Not Applicable in this framework.
PM1	N/A	PM1 is marked Not Applicable by the InSiGHT MLH1 VCEP v2.0.0.
PM2	Met	NM_000249.4:c.1875T>G is absent from gnomAD v4.1 (0 alleles), meeting the InSiGHT VCEP threshold of <0.00002 (fewer than 1 in 50,000 alleles) for PM2_Supporting.	gnomad_v4 gnomad_v2 gnomad_canada
PM5	N/A	PM5 per the InSiGHT VCEP applies to missense changes at an amino acid residue where a different missense change was classified as Pathogenic/Likely Pathogenic. NM_000249.4:c.1875T>G is a nonsense variant.
PM6	N/A	PM6 is marked Not Applicable by the InSiGHT MLH1 VCEP v2.0.0.
PP1	Not met	No co-segregation data are available for this variant.
PP2	N/A	PP2 is marked Not Applicable by the InSiGHT MLH1 VCEP v2.0.0.
PP3	N/A	PP3 per the InSiGHT VCEP applies to missense variants via HCI prior probability or to non-canonical splice variants via SpliceAI. NM_000249.4:c.1875T>G is a nonsense variant with no splice impact (SpliceAI max delta = 0.00).	spliceai
PP4	Not met	No tumor phenotype data (MSI status, IHC for MMR protein expression) are available in the case evidence for this variant.
PP5	Met	Expert panel International Society for Gastrointestinal Hereditary Tumours (InSiGHT) classified as Pathogenic.	clinvar
BA1	Not met	The variant is absent from gnomAD v4.1. The InSiGHT VCEP BA1 threshold requires gnomAD v4 Grpmax filtering allele frequency >= 0.001 (0.1%), which is not met.	gnomad_v4
BS1	Not met	The variant is absent from gnomAD v4.1. The InSiGHT VCEP BS1 threshold requires gnomAD v4 Grpmax filtering allele frequency >= 0.0001 and < 0.001 (0.01-0.1%), which is not met.	gnomad_v4
BS2	Not met	No evidence of co-occurrence in trans with a known pathogenic variant in MLH1 in a patient with colorectal cancer after age 45 and without CMMRD features.
BS3	Not met	No variant-specific functional assay data demonstrating proficient MMR function are available. The variant was not found in the VCEP calibrated functional assay spreadsheet.
BS4	Not met	No segregation data demonstrating lack of co-segregation with disease are available for this variant.
BP1	N/A	BP1 is marked Not Applicable by the InSiGHT MLH1 VCEP v2.0.0.
BP2	N/A	BP2 is marked Not Applicable by the InSiGHT MLH1 VCEP v2.0.0.
BP4	N/A	BP4 per the InSiGHT VCEP applies to missense variants via HCI prior probability <0.11 or to intronic/synonymous variants via SpliceAI delta <= 0.1. NM_000249.4:c.1875T>G is a nonsense variant.	spliceai
BP5	Not met	No tumor phenotype data (MSS status, MMR protein expression, BRAF V600E, or MLH1 methylation status) are available in the case evidence.
BP6	N/A	BP6 is marked Not Applicable by the InSiGHT MLH1 VCEP v2.0.0.
BP7	N/A	BP7 per the InSiGHT VCEP applies to synonymous or intronic variants at or beyond -21/+7. NM_000249.4:c.1875T>G is a nonsense variant.

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