rs587778886
Positions:
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_StrongBS1
The ENST00000413740.2(MLH1):c.-107C>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 0.0000307 in 1,008,238 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 Likely benign (★★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.000031 ( 0 hom. )
Consequence
MLH1
ENST00000413740.2 5_prime_UTR
ENST00000413740.2 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.325
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 -12 ACMG points.
BP6
?
Variant 3-36993441-C-G is Benign according to our data. Variant chr3-36993441-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 89587.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-36993441-C-G is described in Lovd as [Likely_benign]. Variant chr3-36993441-C-G is described in Lovd as [Likely_pathogenic].
BS1
?
Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000307 (31/1008238) while in subpopulation EAS AF= 0.000796 (30/37672). AF 95% confidence interval is 0.000573. There are 0 homozygotes in gnomad4_exome. There are 16 alleles in male gnomad4_exome subpopulation. Median coverage is 14. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLH1 | XM_047448155.1 | upstream_gene_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000413740.2 | c.-107C>G | 5_prime_UTR_variant | 1/15 | 1 | ||||
MLH1 | ENST00000536378.5 | c.-739C>G | 5_prime_UTR_variant | 1/18 | 2 | ||||
MLH1 | ENST00000673673.2 | c.-107C>G | 5_prime_UTR_variant | 1/18 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 0.0000307 AC: 31AN: 1008238Hom.: 0 Cov.: 14 AF XY: 0.0000307 AC XY: 16AN XY: 521466
GnomAD4 exome
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31
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1008238
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16
AN XY:
521466
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
Bravo
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ClinVar
Significance: Likely benign
Submissions summary: Uncertain:2Benign:4
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Oct 09, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 16, 2021 | - - |
Lynch syndrome Benign:1
Likely benign, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | Multifactorial likelihood analysis posterior probability 0.001-0.049 - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jun 15, 2021 | - - |
Computational scores
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Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at