Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
International Society for Gastrointestinal Hereditary Tumours |
RCV000075525 | SCV000106521 | pathogenic | Lynch syndrome | 2013-09-05 | reviewed by expert panel | research | Coding sequence variation resulting in a stop codon |
Invitae | RCV000706709 | SCV000835776 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2022-09-07 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 90040). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 28449805, 28874130). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser698*) in the MLH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 59 amino acid(s) of the MLH1 protein. This variant disrupts a region of the MLH1 protein in which other variant(s) (p.Tyr750*) have been determined to be pathogenic (PMID: 10422993, 16338176, 20533529). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000075525 | SCV000917662 | pathogenic | Lynch syndrome | 2018-08-21 | criteria provided, single submitter | clinical testing | Variant summary: MLH1 c.2093C>G (p.Ser698X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.2141G>A (p.Trp714X), c.2142G>A (p.Trp714X), c.2179_2182delCACA (p.His727fsX55)). The variant was absent in 245618 control chromosomes (gnomAD). c.2093C>G has been reported in the literature in individuals affected with Lynch Syndrome (Rossi 2017, Sunga 2017). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. |
Ambry Genetics | RCV002415539 | SCV002725799 | pathogenic | Hereditary cancer-predisposing syndrome | 2017-08-27 | criteria provided, single submitter | clinical testing | The p.S698* pathogenic mutation (also known as c.2093C>G), located in coding exon 18 of the MLH1 gene, results from a C to G substitution at nucleotide position 2093. This changes the amino acid from a serine to a stop codon within coding exon 18. This mutation has been reported in one Hispanic Lynch syndrome family (Sunga AY et al. Cancer Genet, 2017 Apr;212-213:1-7). 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. |
Myriad Genetics, |
RCV003451103 | SCV004186420 | pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-07-25 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. |
Color Diagnostics, |
RCV002415539 | SCV004359270 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-06-13 | criteria provided, single submitter | clinical testing | This variant changes 1 nucleotide in exon 18 of the MLH1 gene, creating a premature translation stop signal in the last coding exon. This variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. Although functional studies have not been reported, this variant is expected to disrupt the PMS2/MLH3/PMS1 interacting domain (PMID: 12799449, 16338176, 20533529). This variant has been reported in a family affected with Lynch syndrome in El Salvador (PMID: 28874130). 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. |