Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000075435 | SCV000106431 | likely pathogenic | Lynch syndrome | 2019-06-21 | reviewed by expert panel | curation | Multifactorial likelihood analysis posterior probability 0.95-0.99 |
| Invitae | RCV001201396 | SCV000543660 | likely pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2019-10-29 | 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 has been reported to affect MLH1 protein function (PMID: 23403630, 18094436, 15475387). Based on a multifactorial likelihood algorithm using genetic, clinical, in silico and functional data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). This variant has been reported in individuals affected with colorectal cancer (PMID: 14514376, 18094436), and an individual affected with breast cancer (PMID: 25927356) This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with aspartic acid at codon 65 of the MLH1 protein (p.Gly65Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. |
| Ambry Genetics | RCV000564174 | SCV000676062 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2020-11-27 | criteria provided, single submitter | clinical testing | The p.G65D variant (also known as c.194G>A), located in coding exon 2 of the MLH1 gene, results from a G to A substitution at nucleotide position 194. The glycine at codon 65 is replaced by aspartic acid, an amino acid with similar properties. This variant was identified in a Chinese woman with MSI-high colorectal cancer demonstrating loss of MLH1 protein by immunohistochemistry (Fan Y et al. Clin. Cancer Res. 2007 Dec;13:7515-21) and separately in a Chinese patient meeting revised Bethesda criteria for Lynch syndrome (Yang X et al. PLoS ONE 2015 Apr;10:e0125571). In addition, functional analyses have demonstrated at least partial loss of mismatch repair activity associated with this alteration, which is found in the ATP-binding domain (Ellison AR et al. Nucleic Acids Res. 2004 Oct;32:5321-38; Fan Y et al. Clin. Cancer Res. 2007 Dec;13:7515-21; Hinrichsen I et al. Clin. Cancer Res. 2013 May;19:2432-41). This alteration has been classified as likely pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). 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. |