3-36993511-A-G
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The ENST00000413740.2(MLH1):c.-37A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000312 in 1,604,306 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
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000028 ( 0 hom. )
Consequence
MLH1
ENST00000413740.2 5_prime_UTR
ENST00000413740.2 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.294
Genes affected
MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.71).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLH1 | NM_000249.4 | upstream_gene_variant | ENST00000231790.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | upstream_gene_variant | 1 | NM_000249.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152258Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251400Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135904
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GnomAD4 exome AF: 0.00000275 AC: 4AN: 1452048Hom.: 0 Cov.: 29 AF XY: 0.00000415 AC XY: 3AN XY: 723126
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 22, 2016 | This variant is denoted MLH1 c.-37A>G, and describes a nucleotide substitution 37 base pairs upstream of the MLH1 ATG translational start site in the 5' untranslated region (UTR). The surrounding sequence, with the base that is substituted in braces, is GTTG[A/G]GCAT. This variant has not, to our knowledge, been reported in the literature as pathogenic or benign. MLH1 c.-37A>G 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 other 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 nucleotide which is altered, an adenine (A), is conserved among mammals. Based on currently available information, it is unclear whether MLH1 c.-37A>G is pathogenic or benign. We consider it to be a variant of uncertain significance. - |
Computational scores
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at