Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000216198 | SCV000275857 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-01-26 | criteria provided, single submitter | clinical testing | The p.L676P variant (also known as c.2027T>C), located in coding exon 18 of the MLH1 gene, results from a T to C substitution at nucleotide position 2027. The leucine at codon 676 is replaced by proline, an amino acid with some similar properties. This alteration has been identified in HNPCC/Lynch syndrome families and functional studies have shown impaired MLH1 expression, PMS2 interaction, and mismatch-repair activity compared to wild type protein (Betz B et al. J Cancer Res Clin Oncol, 2010 Jan;136:123-34; Hardt K et al, Fam. Cancer 2011 Jun; 10(2):273-84. Köger N et al. Genes Chromosomes Cancer, 2018 Jul;57:350-358; Mangold E et al, Int. J. Cancer 2005 Sep; 116(5):692-702). Studies using human colon carcinoma cell lines have reported conflicting data, showing no defective function in PMS2 interaction and normal subcellular localization of the MLH1 protein (Carneiro da Silva F et al. PLoS One, 2015 Oct;10:e0139753). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV000695668 | SCV000824182 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2022-02-17 | criteria provided, single submitter | clinical testing | Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MLH1 function (PMID: 21404117, 26437357). 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. ClinVar contains an entry for this variant (Variation ID: 90001). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 21404117, 26437257, 28874130). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 676 of the MLH1 protein (p.Leu676Pro). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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. |
| A. |
RCV000075485 | SCV000914325 | uncertain significance | Lynch syndrome | 2019-01-30 | criteria provided, single submitter | research | |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000985781 | SCV001134300 | uncertain significance | not provided | 2018-12-13 | criteria provided, single submitter | clinical testing | |
| Mendelics | RCV000987189 | SCV001136433 | likely pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2024-03-27 | criteria provided, single submitter | clinical testing |