rs193922366
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2
The NM_000249.4(MLH1):c.*35_*37del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.018 in 1,606,042 control chromosomes in the GnomAD database, including 334 homozygotes. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Genomes: 𝑓 0.022 ( 45 hom., cov: 32)
Exomes 𝑓: 0.018 ( 289 hom. )
Consequence
MLH1
NM_000249.4 3_prime_UTR
NM_000249.4 3_prime_UTR
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.0580
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 Benign. Variant got -16 ACMG points.
BP6
?
Variant 3-37050682-GTTC-G is Benign according to our data. Variant chr3-37050682-GTTC-G is described in ClinVar as [Benign]. Clinvar id is 36549.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37050682-GTTC-G is described in Lovd as [Likely_benign]. Variant chr3-37050682-GTTC-G is described in Lovd as [Benign].
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.022 (3345/152290) while in subpopulation AFR AF= 0.0308 (1280/41546). AF 95% confidence interval is 0.0294. There are 45 homozygotes in gnomad4. There are 1629 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 45 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLH1 | NM_000249.4 | c.*35_*37del | 3_prime_UTR_variant | 19/19 | ENST00000231790.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | c.*35_*37del | 3_prime_UTR_variant | 19/19 | 1 | NM_000249.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0219 AC: 3334AN: 152172Hom.: 44 Cov.: 32
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GnomAD3 exomes AF: 0.0168 AC: 4205AN: 250506Hom.: 50 AF XY: 0.0164 AC XY: 2221AN XY: 135464
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GnomAD4 exome AF: 0.0176 AC: 25584AN: 1453752Hom.: 289 AF XY: 0.0175 AC XY: 12660AN XY: 723738
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GnomAD4 genome ? AF: 0.0220 AC: 3345AN: 152290Hom.: 45 Cov.: 32 AF XY: 0.0219 AC XY: 1629AN XY: 74456
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ClinVar
Significance: Benign
Submissions summary: Uncertain:1Benign:10Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not specified Benign:4Other:1
Benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 05, 2016 | - - |
not provided Uncertain:1Benign:3
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | This variant is associated with the following publications: (PMID: 24728327) - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | - - |
Benign, no assertion criteria provided | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 13, 2012 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Lynch syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Benign, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | MAF >1% - |
Benign, criteria provided, single submitter | clinical testing;curation | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 18, 2011 | - - |
Computational scores
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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