3-37020380-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.955G>T(p.Glu319*) variant causes a stop gained 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. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000249.4 stop_gained
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.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:2
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This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Lynch syndrome Pathogenic:1
Coding sequence variation resulting in a stop codon -
not provided Pathogenic:1
This variant is denoted MLH1 c.955G>T at the cDNA level and p.Glu319Ter (E319X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MLH1 Glu319Ter has been observed in associated with colon and gastric cancer (Godino 2001). This variant is considered pathogenic. -
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 90453). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 11748856, 15289847). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu319*) 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). -
Hereditary cancer-predisposing syndrome Pathogenic:1
The p.E319* pathogenic mutation (also known as c.955G>T), located in coding exon 11 of the MLH1 gene, results from a G to T substitution at nucleotide position 955. This changes the amino acid from a glutamic acid to a stop codon within coding exon 11. This alteration has been reported in a Spanish family who met Amsterdam criteria for Lynch syndrome (Godino J et al. Hum. Mutat., 2001 Dec;18:549). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at