rs63750865
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000249.4(MLH1):c.382del(p.Ala128GlnfsTer8) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. A128A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000249.4 frameshift, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLH1 | NM_000249.4 | c.382del | p.Ala128GlnfsTer8 | frameshift_variant, splice_region_variant | 5/19 | ENST00000231790.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | c.382del | p.Ala128GlnfsTer8 | frameshift_variant, splice_region_variant | 5/19 | 1 | NM_000249.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 29
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Lynch syndrome Pathogenic:2
Pathogenic, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | Coding sequence variation resulting in a stop codon - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 25, 2015 | This sequence change deletes 1 nucleotide from exon 5 of the MLH1 mRNA (c.382delG), causing a frameshift at codon 128. This creates a premature translational stop signal (p.Ala128Glnfs*8) and is expected to result in an absent or disrupted protein product. Truncating variants in MLH1 are known to be pathogenic. This particular truncation has been reported in a family with individuals affected with breast cancer and with colon cancer (PMID: 17026620). For these reasons, this variant has been classified as Pathogenic. - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 25, 2015 | For these reasons, this variant has been classified as Pathogenic. Truncating variants in MLH1 are known to be pathogenic. This particular truncation has been reported in a family with individuals affected with breast cancer and with colon cancer  (PMID: 17026620). This sequence change deletes 1 nucleotide from exon 5 of the MLH1 mRNA (c.382delG), causing a frameshift at codon 128. This creates a premature translational stop signal (p.Ala128Glnfs*8) and is expected to result in an absent or disrupted protein product. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at