rs878853794
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000231790.8(MLH1):c.961_962dup(p.Ser321ArgfsTer47) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E319E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
MLH1
ENST00000231790.8 frameshift
ENST00000231790.8 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.52
Genes affected
MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-37020382-G-GGA is Pathogenic according to our data. Variant chr3-37020382-G-GGA is described in ClinVar as [Pathogenic]. Clinvar id is 237352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MLH1 | NM_000249.4 | c.961_962dup | p.Ser321ArgfsTer47 | frameshift_variant | 11/19 | ENST00000231790.8 | NP_000240.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | c.961_962dup | p.Ser321ArgfsTer47 | frameshift_variant | 11/19 | 1 | NM_000249.4 | ENSP00000231790 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jul 18, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Lynch syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 04, 2016 | This sequence change inserts 2 nucleotides in exon 11 of the MLH1 mRNA (c.961_962dupAG), causing a frameshift at codon 321. This creates a premature translational stop signal (p.Ser321Argfs*47) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, truncating variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816 ). For these reasons, this variant has been classified as Pathogenic. - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 01, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 237352). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 26248088). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser321Argfs*47) 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
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 08, 2021 | The c.961_962dupAG pathogenic mutation, located in coding exon 11 of the MLH1 gene, results from a duplication of AG at nucleotide position 961, causing a translational frameshift with a predicted alternate stop codon (p.S321Rfs*47). This alteration (designated as c.962insAG) was reported in one African-American family who met Amsterdam II criteria (Guindalini RS et al. Gastroenterology, 2015 Nov;149:1446-53). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at