Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000075272 | SCV000106266 | pathogenic | Lynch syndrome | 2013-09-05 | reviewed by expert panel | research | Multifactorial likelihood analysis posterior probability >0.99 |
| Ambry Genetics | RCV000130099 | SCV000184929 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2014-02-17 | criteria provided, single submitter | clinical testing | The c.1588_1590delTTC variant (also known as p.F530del) is located in coding exon 14 of the MLH1 gene. This variant results from an in-frame deletion of 3 nucleotides at positions 1588 to 1590 and causes the removal of a highly-conserved phenylalanine residue at codon 1530. This alteration has been described as a pathogenic mutation in Chinese family satisfying Amsterdam criteria for HNPCC/Lynch syndrome (Luo D et al. World J Gastroenterol. 2005 Mar 21;11(11):1673-9). The c.1588_1590delTTC alteration was detected in three family members diagnosed with early-onset CRC (proband and two sons) and was associated with microsatellite instability, but normal MLH1 staining in tumor tissues. This alteration has been classified as definitely pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15). This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 13000 alleles tested) in our clinical cohort (includes this individual). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Invitae | RCV001344767 | SCV001538844 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2020-08-06 | criteria provided, single submitter | clinical testing | Based on a multifactorial likelihood algorithm using genetic data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). This variant has been observed in individual(s) with an increased risk for, or a diagnosis of Lynch syndrome (PMID: 15786548, 28514183). ClinVar contains an entry for this variant (Variation ID: 89798). This variant is not present in population databases (ExAC no frequency). This variant, c.1588_1590del, results in the deletion of 1 amino acid(s) of the MLH1 protein (p.Phe530del), but otherwise preserves the integrity of the reading frame. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Baylor Genetics | RCV003466956 | SCV004195100 | likely pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-09-22 | criteria provided, single submitter | clinical testing |