MLH1 c.1230C>T, p.Ala410=
NM_000249.4:c.1230C>T
Likely Benign
This MLH1 synonymous variant (c.1230C>T; p.Ala410=) has no predicted impact on splicing or protein function (BP4, BP7), is absent/extremely rare in population databases (PM2), and is reported as benign by reputable sources (BP6). Combined benign supporting evidence supports a Likely Benign classification.
ACMG/AMP Criteria Applied
PM2
BP4
BP6
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.1230C>T
Protein Change
A410=
Location
Exon 12
(Exon 12 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.1230C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000398%
Extremely Rare
Highest in Population
Admixed American
0.00289%
Rare
Global: 0.000398%
Admixed American: 0.00289%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251326Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000398%, 1/251326 alleles, homozygotes = 0) and at a higher frequency in the Admixed American population (MAF= 0.00289%, 1/34590 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Likely Benign
Based on 5 submitter reviews in ClinVar
Submitter Breakdown
4 LB
1 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Likely Benign (1 clinical laboratories) and as Benign (1 clinical laboratories).
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: 0.51
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, PVS1 applies to null variants (nonsense, frameshift, canonical ±1–2 splice sites, initiation codon, or multi-exon deletions) predicted to undergo NMD. The evidence for this variant shows a synonymous change (A410=) with no predicted splicing impact. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 applies when a variant results in the same amino acid change as a known pathogenic variant. The evidence for this variant shows no amino acid change (synonymous). Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 applies for confirmed de novo occurrences. There is no reported de novo data for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, PS3 requires validated functional assays showing a deleterious effect. No functional studies are available for this variant. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS4 applies when the variant is significantly enriched in affected individuals. No case-control or segregation data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM1 applies to variants in mutational hotspots or critical functional domains. This synonymous variant does not alter a known functional domain. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset." The evidence for this variant shows MAF = 0.000398% (1/251326 alleles), which is <1/50,000. Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, PM3 applies for recessive disorders with variants in trans. No evidence of trans observations is available. Therefore, this criterion 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 is a synonymous variant with no protein length change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, PM5 applies for novel missense changes at residues with known pathogenic missense variants. This variant is synonymous. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies to assumed de novo cases without confirmation. No such data exist. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 applies for segregation evidence. No family segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies to missense variants in genes with low benign missense variation. This is synonymous. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 (Supporting) applies for predicted splice defect with SpliceAI ≥0.2 or high HCI-prior. SpliceAI delta = 0.02, below threshold. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines for MLH1, PP4 applies for tumor phenotype data (MSI-H or loss of expression). No tumor data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 applies for reputable sources reporting pathogenic. No such report exists for pathogenicity. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 applies for MAF ≥0.001 (0.1%). The variant MAF = 0.000398% is below this threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 applies for MAF ≥0.0001 (0.01%) and <0.001. The variant MAF = 0.000398% is 0.00000398 in fractional terms, below 0.0001. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies for co-occurrence in trans with a pathogenic variant in LS cancers. No such data are available. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 (Strong) applies for functional assays showing no mRNA or protein impact. No functional assays have been performed. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS4 applies for lack of segregation. No segregation data exist. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 applies to missense in genes where only truncating variants cause disease. This is synonymous. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies for observed in trans with a pathogenic variant for a dominant disorder. No such data are available. Therefore, this criterion 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 synonymous variant. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, BP4: "Supporting … For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score <= 0.1 as per Walker et al 2023." The evidence shows SpliceAI delta = 0.02, indicating no splicing impact. Therefore, BP4 is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, BP5 applies for variants found in a case with an alternate molecular basis. No such data are available. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, BP6: "Supporting—Reputable source reports benign, evidence not available to the laboratory." ClinVar reports this variant as Likely benign/Benign by multiple labs. Therefore, BP6 is applied at Supporting strength.
BP7
BP7 (Supporting)
According to VCEP guidelines, BP7: "Supporting—A synonymous (silent) or intronic variant at or beyond -21/+7 (5′/3′ exonic). Variants may satisfy both BP7 and BP4." The variant is synonymous and SpliceAI predicts no splicing impact. Therefore, BP7 is applied at Supporting strength.