Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Department of Pathology and Laboratory Medicine, |
RCV000499458 | SCV000592413 | likely pathogenic | Lynch syndrome | 2014-10-17 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002395211 | SCV002703326 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-03-06 | criteria provided, single submitter | clinical testing | The p.L555R pathogenic mutation (also known as c.1664T>G), located in coding exon 14 of the MLH1 gene, results from a T to G substitution at nucleotide position 1664. The leucine at codon 555 is replaced by arginine, an amino acid with dissimilar properties. The p.L555R pathogenic mutation was reported in a family studied at The Ohio State University and the mutation segregated strongly with disease having an LOD score of 3.03. Ten affected individuals tested positive for the mutation, only one 41 year old unaffected male tested positive for the mutation, and 3 unaffected family members tested negative for the mutation. Tumor analysis performed for individuals in which this alteration was identified revealed high microsatellite instability (MSI-H) or loss of MLH1 and PMS2 protein expression by immunohistochemistry (IHC) (Sturm A.C. et al.; Abstract presented at: Collaborative Group of the Americas on Inherited Colorectal Cancer; 2008 September; Cleveland, OH; Haraldsdottir S et al. Fam. Cancer, 2016 Apr;15:253-60; Roth RM et al. Am. J. Clin. Pathol., 2016 Jul;146:50-6; Haraldsdottir S et al. Genet. Med., 2016 Sep;18:863-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Invitae | RCV003758801 | SCV004536407 | likely pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2023-08-05 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Leu555 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23712482, 31784484). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 433869). This missense change has been observed in individual(s) with colorectal cancer (PMID: 26666765). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 555 of the MLH1 protein (p.Leu555Arg). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MLH1 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. |