rs2241031
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_000249.4(MLH1):c.1990-121C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 979,796 control chromosomes in the GnomAD database, including 86,386 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Genomes: 𝑓 0.40 ( 12934 hom., cov: 32)
Exomes 𝑓: 0.41 ( 73452 hom. )
Consequence
MLH1
NM_000249.4 intron
NM_000249.4 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -3.24
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 -20 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.91).
BP6
?
Variant 3-37048783-C-T is Benign according to our data. Variant chr3-37048783-C-T is described in ClinVar as [Benign]. Clinvar id is 89983.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37048783-C-T is described in Lovd as [Benign].
BA1
?
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.454 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLH1 | NM_000249.4 | c.1990-121C>T | intron_variant | ENST00000231790.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | c.1990-121C>T | intron_variant | 1 | NM_000249.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.403 AC: 61231AN: 151906Hom.: 12928 Cov.: 32
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GnomAD4 exome AF: 0.410 AC: 339731AN: 827772Hom.: 73452 Cov.: 11 AF XY: 0.404 AC XY: 174886AN XY: 432664
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GnomAD4 genome ? AF: 0.403 AC: 61252AN: 152024Hom.: 12934 Cov.: 32 AF XY: 0.395 AC XY: 29361AN XY: 74288
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ClinVar
Significance: Benign
Submissions summary: Benign:3
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not specified Benign:1
Benign, no assertion criteria provided | research | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
Lynch syndrome Benign:1
Benign, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | MAF >1% - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 22, 2018 | - - |
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