rs267607845
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_000249.4(MLH1):c.1668-1G>A variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,448,254 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★★).
Frequency
Consequence
NM_000249.4 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLH1 | NM_000249.4 | c.1668-1G>A | splice_acceptor_variant | ENST00000231790.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | c.1668-1G>A | splice_acceptor_variant | 1 | NM_000249.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000207 AC: 3AN: 1448254Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 721404
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Lynch syndrome Pathogenic:3
Likely pathogenic, reviewed by expert panel | curation | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Jun 21, 2019 | Interrupts canonical donor splice site - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 19, 2019 | The c.1668-1G>A variant in MLH1 has been reported in at least 4 individuals with Lynch Syndrome (Lamberti 2006, Arnold 2009, Pérez-Carbonell 2012, Shirts 2016) and was found to segregate with disease in 2 additional affected individuals in one family (Arnold 2009). This variant was absent from large population studies. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and has been observed to cause altered splicing leading to an abnormal or absent protein (Arnold 2009, Pérez-Carbonell 2012). Heterozygous loss of function of the MLH1 gene is an established disease mechanism in Lynch Syndrome. Additionally, this variant has been classified as Likely pathogenic on Sep 5, 2013 by the ClinGen-approved InSiGHT panel (ClinVar SCV000106296.2). In summary, this variant meets criteria to be classified as pathogenic for Lynch Syndrome in an autosomal dominant manner. ACMG/AMP criteria applied: PM2, PS4_Supporting, PVS1. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | May 01, 2018 | MLH1 NM_000249.3:c.1668-1G>A was observed in one family with several cases of early-onset colon and endometrial cancer (Shirts et al 2016, PMID 26845104). It was also seen as an apparent passenger mutation in a tumor with other somatic mutations apparently responsible for the observed MSI status, reducing the likelihood of pathogenicity (Shirts et al 2018, PMID 29887214). This has been reported as likely pathogenic by the InSiGHT consortium and as pathogenic by several laboratories. We currently consider this variant to be likely pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 19, 2021 | The c.1668-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 15 of the MLH1 gene. This alteration has been previously reported in several individuals with colorectal cancers demonstrating microsatellite instability and absent MLH1 and/or PMS2 IHC staining, including individuals meeting Amsterdam criteria (Taylor CF, et al. Hum. Mutat. 2003 Dec; 22(6):428-33; Piñol V, et al. JAMA 2005 Apr; 293(16):1986-94; Lamberti C, et al. Digestion 2006 ; 74(1):58-67; Pérez-Carbonell L, et al. Gut 2012 Jun; 61(6):865-72; Walker M et al. Br J Surg, 2007 Dec;94:1567-71). One splicing assay using cell lines from mutation carriers found that this alteration results in out-of-frame skipping of exon 15 (Arnold S, et al. Hum. Mutat. 2009 May; 30(5):757-70). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 01, 2022 | This variant causes a G to A nucleotide substitution at the -1 position of intron 14 of the MLH1 gene. Functional RNA studies have shown that this variant causes out-of-frame deletion of exon 15 (PMID: 2707453). This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Lynch syndrome or colorectal cancer with tumors showing microsatellite instability and loss of MLH1 protein expression (PMID: 2707453, 15855432, 17095871, 19267393, 21868491). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | research | Academic Department of Medical Genetics, University of Cambridge | Jan 26, 2018 | Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity. - |
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jul 21, 2023 | This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726]. - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 14, 2023 | ClinVar contains an entry for this variant (Variation ID: 89826). Disruption of this splice site has been observed in individual(s) with Lynch syndrome (PMID: 14635101, 15855432, 17095871, 19267393, 21868491). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 14 of the MLH1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. Studies have shown that disruption of this splice site results in exon skipping and introduces a premature termination codon (PMID: 19267393). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
not provided Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at