MLH1 c.1990-23G>T, p.?
NM_000249.4:c.1990-23G>T
Variant of Uncertain Significance (VUS)
This legacy system is being phased out as Project HERA V3 is rolled out.
ACMG/AMP Criteria Applied
PM2
BS1
BP7
Genetic Information
Gene & Transcript Details
Gene
MLH1
Transcript
NM_000249.4
MANE Select
Total Exons
19
Strand
Forward (+)
Reference Sequence
NC_000003.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000249.3 | RefSeq Select | 19 exons | Forward |
| NM_000249.2 | Alternative | 19 exons | Forward |
Variant Details
HGVS Notation
NM_000249.4:c.1990-23G>T
Protein Change
?
Location
Exon 17
(Exon 17 of 19)
5'Exon Structure (19 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_000249.4
Genome Browser
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HGVS InputNM_000249:c.1990-23G>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000399%
Extremely Rare
Highest in Population
Remaining individuals
0.0164%
Low Frequency
Global: 0.000399%
Remaining individuals: 0.0164%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 250612Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000399%, 1/250612 alleles, homozygotes = 0) and at a higher frequency in the Remaining individuals population (MAF= 0.0164%, 1/6102 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 0.15
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the PVS1 rule applies to canonical ±1/2 splice site variants or null variants in MLH1. The rule states: "Variants at IVS±1 or IVS±2 where exon skipping or use of a cryptic splice site disrupts reading frame...". This variant is located at –23, outside the ±1/2 positions. Therefore, PVS1 is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS1 applies when the variant causes the same amino acid change as a known pathogenic variant. This variant is intronic and does not alter an amino acid. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 applies for confirmed de novo occurrences. No de novo data are available for this variant. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS3 requires well‐established functional studies showing damaging effect. No functional assay data exist for this variant. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS4 applies when variant prevalence is significantly increased in affected individuals versus controls. No case-control or patient frequency data are available. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM1 applies to variants in mutational hot spots or critical functional domains. This intronic variant does not lie in a known hotspot or domain. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, PM2 supporting applies when a variant is absent or extremely rare (<1 in 50,000 alleles) in gnomAD v4. The rule states: "Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset." The variant is observed at 1/250,612 alleles (MAF≈0.00000399), below the threshold. Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 applies for variants observed in trans with a known pathogenic variant in recessive disorders. MLH1-related Lynch syndrome is dominant and no trans data exist. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length changes due to in-frame indels or stop-loss. This variant is intronic with no coding effect. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM5 applies to novel missense changes at residues where other missense changes are pathogenic. This variant is intronic and not missense. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies to assumed de novo variants without confirmation. No de novo assumption data exist. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP1 applies to co-segregation with disease in families. No segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies to missense variants in genes with low rate of benign missense. This variant is intronic. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 supporting applies when SpliceAI predicts a delta score ≥0.2 for non-canonical splice variants. The rule states: "Predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score ≥ 0.2." The variant has a maximum SpliceAI delta of 0.15, below threshold. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 applies to tumor and expression data (MSI-H, loss of MMR protein). No tumor phenotype or IHC data are available. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 applies when reputable sources classify a variant as pathogenic. The variant is not reported in ClinVar or other databases. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 stand‐alone applies for gnomAD v4 filtering allele frequency ≥0.001. The variant’s highest frequency (0.000164) is below this. Therefore, BA1 is not applied.
BS1
BS1 (Strong)
According to VCEP guidelines, BS1 strong applies for gnomAD v4 filtering allele frequency ≥0.0001 and <0.001. The rule states: "GnomAD v4 Grpmax filtering allele frequency ≥ 0.0001 and < 0.001." The variant’s highest frequency is 0.000164, within this range. Therefore, BS1 is applied at Strong strength.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies for co-occurrence in trans with a known pathogenic MLH1 variant in a patient without CMMRD. No co-occurrence data exist. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS3 applies to well‐established functional studies showing no damaging effect. No such assays exist for this variant. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS4 applies to lack of segregation with disease. No segregation data are available. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 applies to missense variants in genes where only loss-of-function is disease mechanism. This variant is intronic. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies when variant is observed in cis with a pathogenic variant. No cis data exist. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. This is a single-nucleotide intronic substitution. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 supporting applies when SpliceAI predicts no splicing impact with delta ≤0.1. The rule states: "SpliceAI predicts no splicing impact with delta score ≤ 0.1." The variant’s maximum delta is 0.15, above threshold. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, BP5 applies to tumor data inconsistent with MLH1 pathogenicity. No tumor or methylation data are available. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies when reputable sources classify a variant as benign. No such classifications exist. Therefore, BP6 is not applied.
BP7
BP7 (Supporting)
According to VCEP guidelines, BP7 supporting applies to intronic variants at or beyond –21 from the exon. The rule states: "A synonymous (silent) or intronic variant at or beyond -21/+7." This variant is at –23. Therefore, BP7 is applied at Supporting strength.