rs267607879
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000249.4(MLH1):c.1989+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Pathogenic (★★★).
Frequency
Genomes: not found (cov: 31)
Consequence
MLH1
NM_000249.4 splice_donor
NM_000249.4 splice_donor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 9.52
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 Pathogenic. Variant got 12 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.04051079 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.3, offset of 31, new splice context is: tcgGTacat. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-37048610-G-A is Pathogenic according to our data. Variant chr3-37048610-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 89973.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37048610-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MLH1 | NM_000249.4 | c.1989+1G>A | splice_donor_variant | ENST00000231790.8 | NP_000240.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | c.1989+1G>A | splice_donor_variant | 1 | NM_000249.4 | ENSP00000231790 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Lynch syndrome Pathogenic:2
Pathogenic, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | Multifactorial likelihood analysis posterior probability >0.99 - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 03, 2022 | The c.1989+1G>A variant in MLH1 has been reported in at least 3 individuals with Lynch syndrome and 1 individual with colerectal cancer (Taylor 2003 PMID: 14635101, Pigatto 2004 PMID: 20233461, Caldes 2004 PMID: 15289847, Mangold 2005 PMID: 15849733). The variant was absent from large population studies. This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the MLH1 gene is an established disease mechanism in Lynch syndrome. The variant has been reported in ClinVar (Variant ID 89973) and has been classified as pathogenic by the InSIGHT expert panel. Two additional variants involving this nucleotide (c.1989+1G>T and c.1989+1G>C) have been identified in individuals with Lynch syndrome and/or colerectal cancer and are classified as pathogenic or likely pathogenic in ClinVar by the InSiGHT expert panel. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch sundrome. ACMG/AMP criteria applied: PVS1_Strong, PM5_Strong, PS4_Moderate, PM2_Supporting. - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 28, 2020 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). This variant has been observed in individuals affected with colorectal cancer (PMID: 14635101, 15289847, 15849733, 20233461). This variant is also known as IVS17+1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 89973). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 17 of the MLH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 15, 2022 | The c.1989+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 17 of the MLH1 gene. This variant has been reported in families with Lynch syndrome and with tumors exhibiting either loss of MLH1 protein on immunohistochemistry or high microsatellite instability (Taylor CF et al. Hum. Mutat., 2003 Dec;22:428-33; Mangold E et al. Int. J. Cancer, 2005 Sep;116:692-702). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D;D;D;D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 30
DS_DL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at