chr3-37011856-T-TA
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000249.4(MLH1):c.588dupA variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000657 in 152,190 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on 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 AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74374
ClinVar
Submissions by phenotype
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:2
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
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Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
This premature translational stop signal has been observed in individual(s) with colorectal cancer (PMID: 21286823). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 972525). This variant is also known as c.643_648dupA. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln197Thrfs*7) 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 c.588dupA pathogenic mutation, located in coding exon 7 of the MLH1 gene, results from a duplication of A at nucleotide position 588, causing a translational frameshift with a predicted alternate stop codon (p.Q197Tfs*7). 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