MLH1 c.1148T>C, p.Met383Thr
NM_000249.4:c.1148T>C
Variant of Uncertain Significance (VUS)
MLH1 c.1148T>C (p.M383T) is an extremely rare missense variant with computational evidence suggesting no functional impact. No functional, segregation, or de novo data are available. The only criteria met are PM2_Supporting and BP4_Supporting, which conflict, resulting in a classification of Variant of Uncertain Significance (VUS).
ACMG/AMP Criteria Applied
PM2
BP4
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.1148T>C
Protein Change
M383T
Location
Exon 12
(Exon 12 of 19)
5'Exon Structure (19 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 383 in gene MLH1
Variant interpretation based on transcript NM_000249.4
Genome Browser
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HGVS InputNM_000249:c.1148T>C
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000708%
Very Rare
Highest in Population
European (non-Finnish)
0.00155%
Rare
Global: 0.000708%
European (non-Finnish): 0.00155%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 282658Alt: 2Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000708%, 2/282658 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.00155%, 2/129048 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
6 publications
Uncertain Significance (VUS)
Based on 9 submitter reviews in ClinVar
Submitter Breakdown
6 VUS
2 LB
1 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (6)
Variant summary: MLH1 c.1148T>C (p.Met383Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251430 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1148T>C has been reported in the literature in individuals affected with ovarian cancer (Pal_2012) and colorectal cancer (Iordache_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33471991, 30324682, 23047549). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS (n=6) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
This missense variant replaces methionine with threonine at codon 383 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with Lynch syndrome-associated cancer or colorectal cancer (PMID: 23047549, 30324682, 31391288). This variant has been identified in 2/282658 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726].
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories) and as Uncertain Significance (1 clinical laboratories) and as Likely benign (2 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
No evidence of other pathogenic variants at position 383 in gene MLH1
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.726
0.726
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 3.23polyphen_prediction: benignmetasvm: Tmetalr: Tprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Strength: Very Strong Nonsense/frameshift variant introducing Premature Termination Codon (PTC) at or before codon 753 in MLH1, or large genomic alterations of single or multi-exon size, or canonical ±1/2 splice site variants leading to NMD." The evidence for this variant shows: it is a missense change (M383T), not a null variant. Therefore, this criterion is not applied because the variant does not result in loss-of-function.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows: no previously established pathogenic variant causes the same M383T amino acid change. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "Well-established functional studies show a deleterious effect on the gene or gene product." The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "The prevalence of the variant in affected individuals is significantly increased compared with controls." The evidence for this variant shows: no case-control or segregation data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hotspot and/or critical and well-established functional domain without benign variation." The evidence for this variant shows: M383 is not within a defined hotspot or critical functional domain under VCEP specifications. 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: allele frequency in gnomAD is 0.000708% (0.00000708) which is below 1 in 50,000 alleles. Therefore, this criterion is applied at Supporting strength because the variant is extremely rare in population databases.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows: no information on trans phase with a pathogenic variant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame indels or stop-loss variants." The evidence for this variant shows: it is a missense substitution without change in protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different missense change is pathogenic." The evidence for this variant shows: no other pathogenic missense changes at residue M383 are established. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, without confirmation of paternity and maternity." The evidence for this variant shows: no de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members." The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation where missense is a common mechanism." The evidence for this variant shows: MLH1 has multiple benign and pathogenic missense variants. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting Missense variant with HCI-prior probability >0.68 & ≤0.81 or predicted splice defect with SpliceAI delta ≥0.2." The evidence for this variant shows: SpliceAI delta score is 0.05 (<0.2) and no high HCI prior. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient's phenotype or family history is highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no tumor phenotype or MSI data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic without available evidence." The evidence for this variant shows: ClinVar submissions are conflicting (VUS, likely benign, benign). Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone GnomAD v4 Grpmax filtering allele frequency ≥0.001 (0.1%) and variant is excluded as a founder pathogenic variant." The evidence for this variant shows: allele frequency 0.00000708 (<0.001). Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong GnomAD v4 Grpmax filtering allele frequency ≥0.0001 and <0.001 (0.01–0.1%)." The evidence for this variant shows: allele frequency 0.00000708 (<0.0001). Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a dominant disorder with full penetrance." The evidence for this variant shows: no such observations reported. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no deleterious effect on the gene or gene product." The evidence for this variant shows: no functional assays performed. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected members of a family." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene for which primarily truncating variants are known to cause disease." The evidence for this variant shows: missense is a known mechanism in MLH1. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant in a dominant disorder." The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in repetitive regions without known function." The evidence for this variant shows: it is a missense substitution. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting Missense variant with HCI-prior probability of pathogenicity <0.11 or for intronic/synonymous variants SpliceAI predicts no splicing impact with delta score ≤0.1." The evidence for this variant shows: SpliceAI delta score is 0.05 (≤0.1) and in silico predictors are predominantly benign. Therefore, this criterion is applied at Supporting strength because computational evidence suggests no impact.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no alternate molecular diagnosis reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign without available evidence." The evidence for this variant shows: ClinVar submissions are conflicting and not definitively benign. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting synonymous or intronic variant at or beyond -21/+7 positions with no predicted splicing impact." The evidence for this variant shows: it is a missense substitution. Therefore, this criterion is not applied.