Total submissions: 12
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Counsyl | RCV000411311 | SCV000487919 | likely pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2015-12-07 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV000684819 | SCV000543574 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2023-12-30 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Gln407*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with sebaceous gland cancer and colorectal cancer and Lynch syndrome (PMID: 26248088, 27601186). ClinVar contains an entry for this variant (Variation ID: 371799). For these reasons, this variant has been classified as Pathogenic. |
Gene |
RCV000486818 | SCV000571217 | pathogenic | not provided | 2020-04-21 | criteria provided, single submitter | clinical testing | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with MLH1-related cancers (Guindalini 2015, Lagerstedt-Robinson 2016); This variant is associated with the following publications: (PMID: 28984303, 27601186, 26248088, 30989425) |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001731666 | SCV000919637 | pathogenic | Hereditary nonpolyposis colon cancer | 2021-09-23 | criteria provided, single submitter | clinical testing | Variant summary: MLH1 c.1219C>T (p.Gln407X) 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. The variant was absent in 251336 control chromosomes. c.1219C>T has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and suspected HNPCC (Guindalini_2015, Lagerstedt-Robinson_2016, Xicola_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000486818 | SCV001134288 | pathogenic | not provided | 2018-10-07 | criteria provided, single submitter | clinical testing | The variant creates a premature nonsense codon, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and not found in general population data. |
Color Diagnostics, |
RCV001183269 | SCV001348953 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-11-15 | criteria provided, single submitter | clinical testing | This variant changes 1 nucleotide in exon 12 of the MLH1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals and families affected with Lynch syndrome or Lynch-syndrome associated cancer (PMID: 26248088, 27601186, 30989425). 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. |
Ambry Genetics | RCV001183269 | SCV002658680 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-11-28 | criteria provided, single submitter | clinical testing | The p.Q407* pathogenic mutation (also known as c.1219C>T), located in coding exon 12 of the MLH1 gene, results from a C to T substitution at nucleotide position 1219. This changes the amino acid from a glutamine to a stop codon within coding exon 12. This alteration has been seen in multiple Lynch syndrome patients and families (Guindalini RS et al. Gastroenterology, 2015 Nov;149:1446-53; Lagerstedt-Robinson K et al. Oncol. Rep., 2016 Nov;36:2823-2835). This variant is considered to be rare based on population 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. |
Myriad Genetics, |
RCV000411311 | SCV004020236 | pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-03-10 | 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. |
Mayo Clinic Laboratories, |
RCV000486818 | SCV004224638 | pathogenic | not provided | 2022-04-27 | criteria provided, single submitter | clinical testing | PM2, PVS1 |
All of Us Research Program, |
RCV003995908 | SCV004840977 | pathogenic | Lynch syndrome | 2024-01-08 | criteria provided, single submitter | clinical testing | This variant changes 1 nucleotide in exon 12 of the MLH1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals and families affected with Lynch syndrome or Lynch-syndrome associated cancer (PMID: 26248088, 27601186, 30989425). 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. |
Neuberg Centre For Genomic Medicine, |
RCV000411311 | SCV005061114 | pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | criteria provided, single submitter | clinical testing | The observed stop gained c.1219C>T(p.Gln407Ter) variant in MLH1 gene has been reported previously in heterozygous state in individual(s) affected with colorectal cancer and Lynch syndrome (Lagerstedt-Robinson et al., 2016). This variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submitters). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MLH1 are known to be pathogenic (Thompson et al., 2014). For these reasons, this variant has been classified as Likely Pathogenic. Computational evidence (MutationTaster - Disease causing) predicts damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Pathogenic. | |
Department of Pathology and Laboratory Medicine, |
RCV000486818 | SCV000592401 | pathogenic | not provided | no assertion criteria provided | clinical testing |