chr3-36993506-C-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
The ENST00000413740.2(MLH1):c.-42C>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 0.000112 in 1,597,998 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 0.000098 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00011 ( 0 hom. )
Consequence
MLH1
ENST00000413740.2 5_prime_UTR
ENST00000413740.2 5_prime_UTR
Scores
1
1
Clinical Significance
Conservation
PhyloP100: 2.46
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 -4 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.53).
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: 0.0000985 AC: 15AN: 152252Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251350Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135888
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GnomAD4 exome AF: 0.000113 AC: 164AN: 1445628Hom.: 0 Cov.: 28 AF XY: 0.000105 AC XY: 76AN XY: 720464
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1Uncertain:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2003 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 30, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jun 21, 2016 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 06, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 17, 2023 | Describes a nucleotide substitution 42 base pairs upstream of the ATG translational start site; Published functional studies are conflicting: demonstrates reduced promoter activity in experimental cell lines while cDNA analysis from one carrier showed MLH1 expression was not impacted (Green et al., 2003; Ward et al., 2013; Morak et al., 2018); Observed in individuals with suspected Lynch syndrome, some with colon tumors showing loss of MLH1 expression by immunohistochemistry (IHC) (Green et al., 2003; Mangold et al., 2005; Ward et al., 2013; Yurgelun et al., 2015; Morak et al., 2018); Has no predicted effect on splicing and the nucleotide is not conserved; This variant is associated with the following publications: (PMID: 11726306, 15849733, 22878509, 12919137, 26332594, 25980754, 25762362, 26888055, 23462881, 28640387, 29472279, 29490919, 32719484, 17895478) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 18, 2018 | The c.-42C>T variant in MLH1 has been reported in 5 individuals with colorectal cancer (Green 2003, Mangold 2005, Ward 2013, Yurgelun 2015, Morak 2018), and seg regated with disease in two individuals from 1 family (Green 2003). This variant has been reported by other clinical laboratories in ClinVar (Variation ID: 8959 3) and has also been identified in 0.01% (12/126682) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). The c.-42C>T variant is located in th e 5' UTR, but its effect on translation is unknown. In vitro functional studies provide some evidence that it may impact protein function (Green 2003, Ward 2013 ). In summary, the clinical significance of the c.-42C>T variant is uncertain. A CMG/AMP Criteria applied: PS3_Supporting, PS4_Supporting. - |
Familial colorectal cancer Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MLH1 c.-42C>T variant was identified in 5 of 7756 proband chromosomes (frequency: 0.0006) from individuals or families with colorectal cancer (Morak 2018, Green 2003, Yurgelun 2015, Ward 2013, Mangold 2005). The variant was identified in dbSNP (rs41285097) as 'Auwith uncertain significance allele' and ClinVar (classified as uncertain significance by Invitae, Counsyl, Ambry Genetics, PreventionGenetics, GeneDx, Partners Healthcare and OMIM). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 14 of 268,324 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 13 of 118,166 chromosomes (freq: 0.0001) and African in 1 of 23,618 chromosomes (freq: 0.00004); it was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, Other or South Asian populations. The variant was identified in two affected members of a family with colorectal cancer, one of whom had an MLH1-deficient tumour (Green 2003). In addition, the variant was demonstrated to significantly reduce, but not abolish, MLH1 transcriptional activity; however, the effect on translation is not known (Green 2003, Ward 2013). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 27, 2021 | - - |
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 16, 2020 | This variant occurs in a non-coding region of the MLH1 gene. It does not change the encoded amino acid sequence of the MLH1 protein. This variant is present in population databases (rs41285097, ExAC 0.005%). This variant has been observed in individual(s) with clinical features of autosomal dominant Lynch syndrome (PMID: 12919137, 11726306, 29472279, 22878509). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 89593). This variant has been reported to have conflicting or insufficient data to determine the effect on MLH1 protein function (PMID: 12919137, 22878509). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 03, 2018 | The c.-42C>T variant is located in the 5' untranslated region (5’ UTR) of the MLH1 gene. This variant results from a C to T substitution 42 nucleotides upstream from the first translated codon. This alteration has been reported in multiple suspected-HNPCC/Lynch syndrome patients to date; however microsatellite instability (MSI) and immunohistochemistry (IHC) results from these individuals have been inconsistent (Müller-Koch Y et al. Eur. J. Med. Res. 2001; 6:473-82, Green RC et al. Clin. Genet. 2003; 64:220-7, Mangold E et al. Int. J. Cancer 2005; 116:692-702, Ward RL et al. Genet. Med. 2013; 15:25-35). Artificial promoter reporter assays have shown a c.-42C>T-associated reduction in activity between 37-80% of wild type levels (Green RC et al. Clin. Genet. 2003; 64:220-7, Ward RL et al. Genet. Med. 2013; 15:25-35). This nucleotide position is well conserved in available vertebrate species. Since supporting evidence is limited and conflicting at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
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Name
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at