Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000573430 | SCV000669605 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-10-03 | criteria provided, single submitter | clinical testing | The p.L585P variant (also known as c.1754T>C), located in coding exon 16 of the MLH1 gene, results from a T to C substitution at nucleotide position 1754. The leucine at codon 585 is replaced by proline, an amino acid with similar properties. This variant has been reported in a female proband who did not meet Amsterdam criteria (AC) or Bethesda guidelines for Lynch syndrome, but did have loss of MLH1 protein expression in her colorectal tumor by immunohistochemistry (IHC) (Jiang W et al. Int J Cancer, 2019 05;144:2161-2168). This variant was also identified in a proband whose family history met ACII for Lynch syndrome and colorectal tumor demonstrated loss of both MLH1/PMS2 protein expression by IHC (Ambry internal data). Based on internal structural analysis, L585P results in decreased structural stability (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Labcorp Genetics |
RCV003758827 | SCV004509262 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-02-14 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 585 of the MLH1 protein (p.Leu585Pro). 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. 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: 483581). This missense change has been observed in individual(s) with colorectal cancer (PMID: 30521064). This variant is not present in population databases (gnomAD no frequency). |
| Ding PR Lab, |
RCV001093657 | SCV001250837 | uncertain significance | Lynch syndrome 1 | no assertion criteria provided | clinical testing |