NM_000249.4:c.1990-23G>T

MLH1 · NP_000240.1:p.? · NM_000249.4

GRCh37: chr3:37090372 G>T · GRCh38: chr3:37048881 G>T

Gene: MLH1 Transcript: NM_000249.4

Final call

BS1_Strong BP4_Supporting BP7_Supporting PM2_Supporting

Variant details

Gene

MLH1

Transcript

NM_000249.4

Protein

NP_000240.1:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

The MLH1 c.1990-23G>T (p.?) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.

In gnomAD v4.1, this variant is very rare overall at 6/1539510 alleles (AF 0.00000389734), which is below the MLH1 PM2_Supporting threshold of 0.00002, but the gnomAD v4.1 grpmax filtering allele frequency is 0.00013658 in the Middle Eastern population, which falls within the MLH1 BS1 range of 0.0001 to less than 0.001; gnomAD v2.1 also shows only 1/250612 alleles (AF 0.00000399023).

No variant-specific functional or constitutional RNA assay evidence was identified for this variant, so PS3 and BS3 were not assessed.

SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, which is below the BP4 threshold of 0.1 and below the PP3 threshold of 0.2, and the intronic position c.1990-23 is beyond the BP7 distance threshold of -21.

Final determination: Under the MLH1 InSiGHT ACMG/AMP combination framework, the presence of BS1_Strong together with PM2_Supporting results in Uncertain Significance because benign strong and pathogenic supporting evidence are conflicting.

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
BP6	N/A	BP6 is not used in the MLH1 InSiGHT hereditary colorectal cancer/polyposis specification.	case_summary.json:cspec.criteria[BP6] prefetch.json:steps.cspec.criteria[BP6]
PS3	Not assessed	No variant-specific calibrated functional assay, RNA study, or monoallelic expression result was identified for this MLH1 intronic variant, so pathogenic functional evidence cannot be applied.	literature_pass.json vcep_materials.json prefetch.json:steps.cspec.criteria[PS3]
PM3	Not assessed	No evidence was identified showing this variant in trans with a pathogenic or likely pathogenic MLH1 variant in an individual with features consistent with constitutional mismatch repair deficiency, so PM3 cannot be assessed.	literature_pass.json prefetch.json:steps.cspec.criteria[PM3] vcep_materials.json
PP5	N/A	PP5 is not used in the MLH1 InSiGHT hereditary colorectal cancer/polyposis specification.	case_summary.json:cspec.criteria[PP5] prefetch.json:steps.cspec.criteria[PP5]
PP4	Not assessed	No tumor microsatellite instability result, mismatch repair immunohistochemistry pattern, or MLH1 promoter methylation result was identified, so phenotype-specific tumor evidence for PP4 was not available.	literature_pass.json prefetch.json:steps.cspec.criteria[PP4]
BA1	Not met	The gnomAD v4.1 grpmax filtering allele frequency is 0.00013658, which is below the BA1 threshold of 0.001, so stand-alone benign population evidence is not met.	evidence.json:results.gnomad.GNOMAD_V4_1
PS1	Not assessed	No previously established pathogenic or likely pathogenic variant affecting this same non-canonical splice nucleotide with similar or greater predicted splice impact was identified in the reviewed materials, so PS1 was not applied.	prefetch.json:steps.cspec.criteria[PS1] vcep_db/MLH1/files/VCEP-pilot-variants---MMR.xlsx
PP2	N/A	PP2 is not applicable for this MLH1 specification.	case_summary.json:cspec.criteria[PP2] prefetch.json:steps.cspec.criteria[PP2]
PM5	N/A	PM5 is a missense-residue rule and does not apply to this intronic variant.	case_summary.json:normalization prefetch.json:steps.cspec.criteria[PM5]
PS2	Not assessed	No confirmed de novo occurrence data were identified for this variant, so PS2 cannot be assessed.	literature_pass.json prefetch.json:steps.cspec.criteria[PS2]
BP3	N/A	BP3 is not applicable for this MLH1 specification.	case_summary.json:cspec.criteria[BP3] prefetch.json:steps.cspec.criteria[BP3]
PP1	Not assessed	No segregation data were identified, so co-segregation evidence for PP1 could not be assessed.	literature_pass.json prefetch.json:steps.cspec.criteria[PP1]
BP5	Not assessed	No tumor data were identified showing microsatellite-stable disease, intact mismatch repair protein expression, inconsistent mismatch repair loss, or MLH1 methylation/BRAF V600E findings that would support BP5.	literature_pass.json prefetch.json:steps.cspec.criteria[BP5]
BS1	Met	In gnomAD v4.1, the grpmax filtering allele frequency is 0.00013658, which is within the BS1 range of 0.0001 to less than 0.001. No evidence was identified that this variant is a known founder pathogenic variant, so BS1 is met.	evidence.json:results.gnomad.GNOMAD_V4_1 evidence.json:results.clinvar literature_pass.json
PVS1	Not met	This variant is a non-canonical intronic change at c.1990-23 rather than a canonical +/-1 or +/-2 splice-site variant, truncating variant, initiation codon variant, or exon-level deletion/duplication, and no RNA evidence of a loss-of-function splice defect was identified. Available evidence does not support PVS1.	case_summary.json:normalization evidence.json:results.spliceai prefetch.json:steps.cspec.criteria[PVS1]
BP2	N/A	BP2 is not applicable for this MLH1 specification.	case_summary.json:cspec.criteria[BP2] prefetch.json:steps.cspec.criteria[BP2]
PM4	N/A	PM4 is not applicable for this MLH1 specification.	case_summary.json:cspec.criteria[PM4] prefetch.json:steps.cspec.criteria[PM4]
BP4	Met	SpliceAI predicts no significant splice impact for this intronic variant, with a maximum delta score of 0.00, which is below the BP4 threshold of 0.1. This supports BP4.	evidence.json:results.spliceai prefetch.json:steps.cspec.criteria[BP4]
PP3	Not met	SpliceAI predicts no significant splice impact, with a maximum delta score of 0.00, which is below the PP3 threshold of 0.2 for a predicted splice defect. Available in silico evidence does not support PP3.	evidence.json:results.spliceai prefetch.json:steps.cspec.criteria[PP3]
BP7	Met	This is an intronic variant at c.1990-23, which is beyond the BP7 distance threshold of -21 for 5′ intronic positions. This supports BP7.	case_summary.json:normalization prefetch.json:steps.cspec.criteria[BP7]
PM6	N/A	PM6 is not applicable for this MLH1 specification.	case_summary.json:cspec.criteria[PM6] prefetch.json:steps.cspec.criteria[PM6]
PM1	N/A	PM1 is not applicable for this MLH1 specification.	case_summary.json:cspec.criteria[PM1] prefetch.json:steps.cspec.criteria[PM1]
BS2	Not assessed	No evidence was identified showing this variant in trans with a known pathogenic MLH1 variant in an older affected individual without features of constitutional mismatch repair deficiency, so BS2 could not be assessed.	literature_pass.json prefetch.json:steps.cspec.criteria[BS2] vcep_materials.json
BP1	N/A	BP1 is not applicable for this MLH1 specification.	case_summary.json:cspec.criteria[BP1] prefetch.json:steps.cspec.criteria[BP1]
BS4	Not assessed	No informative lack-of-segregation data were identified, so BS4 could not be assessed.	literature_pass.json prefetch.json:steps.cspec.criteria[BS4]
BS3	Not assessed	No variant-specific laboratory evidence showing normal mRNA splicing, no allelic imbalance, or proficient function was identified, so benign functional evidence could not be applied.	literature_pass.json vcep_materials.json prefetch.json:steps.cspec.criteria[BS3]
PS4	N/A	PS4 is not applicable for this MLH1 specification.	case_summary.json:cspec.criteria[PS4] prefetch.json:steps.cspec.criteria[PS4]
PM2	Met	In gnomAD v4.1, this variant is present in 6 of 1,539,510 alleles with a total allele frequency of 0.00000389734, which is below the PM2_Supporting threshold of 0.00002. This supports PM2 at supporting strength.	evidence.json:results.gnomad.GNOMAD_V4_1 prefetch.json:steps.cspec.criteria[PM2]

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.