chr3-36993505-C-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
The ENST00000413740(MLH1):c.-43C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000376 in 1,597,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
ENST00000413740 5_prime_UTR
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152262Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000277 AC: 4AN: 1445528Hom.: 0 Cov.: 28 AF XY: 0.00000139 AC XY: 1AN XY: 720402
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152262Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74392
ClinVar
Submissions by phenotype
not provided Uncertain:1
This variant is denoted MLH1 c.-43C>T, and describes a nucleotide substitution 43 base pairs upstream of the MLH1 ATG translational start site in the 5' untranslated region (UTR). This variant has been reported in at least one individual undergoing multigene hereditary cancer panel testing due to the suspicion of Lynch syndrome (Yurgelun 2015). This variant does not appear to affect the start codon or the Kozak translational consensus sequence. Of note, constitutional epigenetic silencing of MLH1 has been suggested as an alternate mechanism responsible for Lynch syndrome and variants located within the 5' UTR have been shown to result in allele specific promoter methylation and subsequent transcriptional silencing (Hitchins 2011, Ward 2013). This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The base that is alternated, a cysteine (C), is not conserved. At this time, we consider MLH1 c.-43C>T to be a variant of uncertain significance. -
Hereditary cancer-predisposing syndrome Uncertain:1
There is insufficient or conflicting evidence for classification of this alteration. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at