Variant classification summary

NM_000249.4:c.2044_2045del

MLH1 · NP_000240.1:p.(Met682ValfsTer11) · NM_000249.4

GRCh37: chr3:37090447 CTA>C · GRCh38: chr3:37048956 CTA>C

Gene: MLH1 Transcript: NM_000249.4

Final call

VUS

PVS1 very strong PM2 supporting

Variant details

Gene

MLH1

Transcript

NM_000249.4

Protein

NP_000240.1:p.(Met682ValfsTer11)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

MLH1 c.2044_2045del (p.Met682ValfsTer11) is a frameshift deletion in exon 18 that introduces a premature termination codon at codon 693, upstream of codon 753, meeting PVS1 at very strong strength under the InSiGHT MLH1 specification.

2

The variant is absent from gnomAD v2.1 and v4.1, meeting PM2 at supporting strength.

3

The variant has been reported in ClinVar as Pathogenic (6 clinical laboratories; ClinVar VariationID 237329) and has been observed in Hispanic families with Lynch syndrome.

4

No variant-specific functional, segregation, or tumor phenotype data were identified; PS3, PP1, and PP4 are not met, and all benign criteria are not met.

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 v2.0 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	Met	MLH1 c.2044_2045del (p.Met682ValfsTer11) is a frameshift deletion in exon 18 that introduces a premature termination codon at codon 693, upstream of codon 753, meeting PVS1 at very strong strength under the InSiGHT MLH1 specification.	cspec pvs1_variant_assessment pvs1_gene_context
PS1	N/A	PS1 applies to missense substitutions encoding the same amino acid change or to splice-site variants; this is a frameshift deletion.
PS2	Not met	No de novo observation with confirmed maternity/paternity was identified for this variant.
PS3	Not met	No variant-specific functional assay or systematically characterized residue range includes this variant; available functional literature tests other MLH1 missense variants and does not characterize this position.	oncokb
PS4	N/A	PS4 is not applicable under the InSiGHT MLH1 specification.
PS5	N/A	PS5 (de novo) is not used in this VCEP; de novo evidence is assessed under PS2, and no de novo data exist.
PM1	N/A	PM1 is not applicable under the InSiGHT MLH1 specification.
PM2	Met	The variant is absent from gnomAD v2.1 and v4.1, meeting PM2 at supporting strength (allele frequency <0.00002).	gnomad_v2 gnomad_v4
PM4	N/A	PM4 is not applicable under the InSiGHT MLH1 specification.
PM5	N/A	PM5 applies to missense substitutions at a residue with a known pathogenic missense change; this is a frameshift deletion with no missense comparator.	pm5_candidates
PM6	N/A	PM6 is not applicable under the InSiGHT MLH1 specification.
PP1	Not met	No co-segregation data with a computed Bayes likelihood ratio is available for this variant.
PP2	N/A	PP2 is not applicable under the InSiGHT MLH1 specification.
PP3	N/A	PP3 (HCI prior or SpliceAI-based splice prediction) applies to missense or splice variants; this is a frameshift deletion with a SpliceAI max delta of 0.00.	spliceai
PP4	Not met	No MSI-H tumor or MMR protein expression loss data specific to this variant is available in the reviewed abstracts.
PP5	N/A	PP5 is not applicable under the InSiGHT MLH1 specification, and the ClinVar record is 'criteria provided, single submitter' (not a 3-star expert panel).	clinvar
BA1	Not met	The variant is absent from gnomAD and does not reach the BA1 allele frequency threshold (>=0.001).	gnomad_v4
BS1	Not met	The variant is absent from gnomAD and does not reach the BS1 allele frequency threshold (0.01-0.1%).	gnomad_v4
BS2	Not met	No observation of this variant in trans with a known pathogenic MLH1 variant in an individual without CMMRD has been reported.
BS3	Not met	No functional evidence demonstrating normal/proficient MMR function for this variant is available.
BS4	Not met	No lack-of-co-segregation data is available for this variant.
BP1	N/A	BP1 is not applicable under the InSiGHT MLH1 specification.
BP2	N/A	BP2 is not applicable under the InSiGHT MLH1 specification (BS2 is used instead).
BP3	N/A	BP3 is not applicable under the InSiGHT MLH1 specification (in-frame deletion in repetitive region); this is an out-of-frame deletion.
BP4	N/A	BP4 (HCI prior or SpliceAI benign prediction) applies to missense, synonymous, or intronic variants; this is a frameshift deletion.	spliceai
BP5	Not met	No alternate molecular basis (MSS tumor, BRAF V600E, or MLH1 methylation) has been reported for this variant.
BP6	N/A	BP6 is not applicable under the InSiGHT MLH1 specification, and the ClinVar record is 'criteria provided, single submitter' (not a 3-star expert panel).	clinvar
BP7	N/A	BP7 applies to synonymous or intronic variants at/beyond the -21/+7 splice region; this is a frameshift deletion.
PM3	N/A	Skipped; recessive/CMMRD co-occurrence criterion, not applicable for this dominant Lynch syndrome frameshift assessment.

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