3-37014545-G-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000249.4(MLH1):c.790+1G>T variant causes a splice donor, intron 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
Consequence
NM_000249.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 24
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1
This variant is considered pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 8574961, 16395668, 11781295]. 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
This sequence change affects a donor splice site in intron 9 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. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with clinical features of Lynch syndrome (PMID: 9833759, 11524701, 15849733, 25530820, 26895986, 28874130). ClinVar contains an entry for this variant (Variation ID: 141043). Studies have shown that disruption of this splice site results in skipping of exon 9 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.790+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 9 of the MLH1 gene. Other variants at the same splice donor site consensus sequences, c.790+1G>A and c.790+2DUPT, have been reported as pathogenic based on being identified in individuals meeting Amsterdam criteria and from functional studies utilizing patient RNA that demonstrate these alterations lead to skipping of coding exons 9 and 10 (Liu B et al. Nat. Med. 1996 Feb;2(2):169-74; Southey MC et al. J. Clin. Oncol., 2005 Sep;23:6524-32; Jenkins MA et al. Clin. Gastroenterol. Hepatol., 2006 Apr;4:489-98; Auclair J et al. Hum. Mutat. 2006 Feb;27:145-54; Arnold S et al. Hum. Mutat., 2009 May;30:757-70; Rosty C et al. BMJ Open. 2016 Feb;6(2):e010293; Ambry internal data). This alteration has been identified as somatic in conjunction with MLH1 copy neutral loss of heterozygosity (CN-LOH) in colorectal as well as uterine tumors that showed loss of both MLH1/PMS2 expression by immunohistochemistry and MLH1 promotor hypermethylation was negative (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this variant will weaken the native splice donor site. RNA studies have demonstrated that this variant results in abnormal splicing in the set of samples tested (Ambry internal data). In addition to the clinical data presented in the literature, variants 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 variant is classified as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at