Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000075390 | SCV000106385 | pathogenic | Lynch syndrome | 2019-02-21 | reviewed by expert panel | curation | Multifactorial likelihood analysis posterior probability >0.99 (1.000) |
| Invitae | RCV001201390 | SCV000254361 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2022-06-03 | 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 622 of the MLH1 protein (p.Leu622Pro). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu622 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11748856, 17510385, 20858721, 23403630, 24362816). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects MLH1 function (PMID: 30998989). 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: 89911). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 1749856, 21404117; Invitae). |
| Ambry Genetics | RCV002408581 | SCV002723391 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2019-01-21 | criteria provided, single submitter | clinical testing | The p.L622P variant (also known as c.1865T>C), located in coding exon 16 of the MLH1 gene, results from a T to C substitution at nucleotide position 1865. The leucine at codon 622 is replaced by proline, an amino acid with similar properties. This alteration has been reported in a patient with breast and colorectal cancer who met Bethesda criteria for Lynch syndrome and whose colorectal tumor showed loss of MLH1 and PMS2 proteins on immunohistochemical (IHC) analysis (Koehler U et al. Cancer Genet. Cytogenet., 2007 May;175:81-4). This alteration was also reported in an individual diagnosed with colon cancer at 43 who met Amsterdam II criteria for Lynch syndrome. This individual's colon tumor displayed high microsatellite instability (MSI-H) with loss of both MLH1/PMS2 on IHC analysis and co-occurrence with another MLH1 missense alteration was identified, p.A623S, but the phase (whether in cis or trans) was not reported (Hardt K et al. Fam. Cancer, 2011 Jun;10:273-84). This alteration was also identified as somatic in a MSI-H colon tumor that displayed loss of MLH1 and PMS2 on IHC analysis (Ambry internal data). Based on an internal structural assessment, this alteration leads to destabilization of the C-terminal domain. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60) and pathogenic by the PON-MMR prediction tool (Ali H et al. Hum. Mutat., 2012 Apr;33:642-50). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |