chr3-37001045-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001167618.3(MLH1):c.-426C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000125 in 1,595,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Consequence
NM_001167618.3 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152094Hom.: 0 Cov.: 32
GnomAD4 exome AF: 6.93e-7 AC: 1AN: 1443406Hom.: 0 Cov.: 27 AF XY: 0.00000139 AC XY: 1AN XY: 719290
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152094Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74302
ClinVar
Submissions by phenotype
not provided Pathogenic:7
- -
- -
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (PMID: 10480359, 10995807, 11606497, 15872200, 15849733, 15955785, 17267619, 17312306, 19419416, 25980754, 27601186, 27965287, 29238914); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15872200, 17312306, 17267619, 10995807, 29950348, 30382883, 34343771, 31830689, 33858029, 29758216, 30998989, 25525159, 10480359, 18415027, 25980754, 15955785, 15849733, 15235038, 15475387, 11606497, 19419416, 27601186, 27965287, 29866690, 29238914, 33087929, 33047316, 33471991) -
- -
This nonsense variant causes the premature termination of MLH1 protein synthesis. The frequency of this variant in the general population, 0.0000087 (1/114534 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in multiple individuals and families affected with Lynch syndrome (PMID: 25980754 (2015), 21642682 (2011), 17453009 (2007), 17312306 (2007), 17267619 (2007), 15955785 (2005), 15872200 (2005), 15849733 (2005), 15235038 (2004), 11606497 (2001), 10995807 (2000)). Based on the available information, this variant is classified as pathogenic. -
- -
- -
Lynch syndrome Pathogenic:4
The p.Arg100X variant in MLH1 has been reported in at least 10 individuals with Lynch syndrome and segregated with disease in at least 6 affected individuals from 2 families (Wang 1999, Samowitz 2001, Renknen 2003, Renkonen 2004, Taylor 2003 Mangold 2005, Choi 2009, Hampel 2005, Lagerstedt 2007, Peel 2000, Gylling 2007). It was absent from large population studies. This variant was classified as Pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 36550). This nonsense variant leads to a premature termination codon at position 100, which is predicted to lead to a truncated or absent protein. Loss of function of the MLH1 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate, PP1_Moderate. -
The MLH1 p.Arg100X variant was identified in 10 of 8938 proband chromosomes from individuals with colon or gastric cancer and was absent in 146 control chromosomes (Choi 2009, Gylling 2007, Hampel 2005, Lagerstedt Robinson 2007, Mangold 2005, Peel 2000, Samowitz 2001, Taylor 2003). The variant was also identified in dbSNP (ID: rs63751221) “With pathogenic allele”, HGMD, UMD (44X), “Mismatch Repair Genes Variant Database”, and the COSMIC database. The p.Arg100X variant leads to a premature stop codon at position 100, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MLH1 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. Three studies showed microsatellite instability in tumours from patients positive for the variant (Gylling 2007, Hampel 2005, Samowitz 2001); Gylling (2007) also showed loss of heterozygosity of MLH1 in the tumour analysed. In addition, Lagerstedt Robinson (2007) demonstrated a loss of MLH1 protein expression in a tumour from a patient with the variant. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -
- -
Coding sequence variation resulting in a stop codon -
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:3
- -
- -
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Hereditary cancer-predisposing syndrome Pathogenic:2
This variant changes 1 nucleotide in exon 3 of the MLH1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. 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. -
The c.298C>T (p.R100*) alteration, located in exon 3 (coding exon 3) of the MLH1 gene, consists of a C to T substitution at nucleotide position 298. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 100. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This mutation is well described in the literature and has been reported in multiple individuals and families with hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome (Taylor, 2003; Renkonen, 2004; Hampel, 2005; Mangold, 2005; Lagerstedt Robinson, 2007; Gylling, 2007; Choi, 2009; Bonadona, 2011; Stojcev, 2013; Kamiza, 2015; Guindalini, 2015; Azizi, 2018). In one study, this variant was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Breast Cancer Association, 2021). Of note, this alteration is also designated as "100 Arg>stop (CGA>TGA)," R100X, and p.Arg100X in published literature. Based on the available evidence, this alteration is classified as pathogenic. -
Lynch-like syndrome Pathogenic:1
- -
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
This sequence change creates a premature translational stop signal (p.Arg100*) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 10480359, 11606497, 14512394, 15235038, 15872200, 17312306). It has also been observed to segregate with disease in related individuals. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MLH1 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MLH1 testing. ClinVar contains an entry for this variant (Variation ID: 36550). Studies have shown that this premature translational stop signal is associated with inconclusive levels of altered splicing (internal data). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at