Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000075115 | SCV000106106 | pathogenic | Lynch syndrome | 2013-09-05 | reviewed by expert panel | research | Abrogated function, >2 MSI-H tumours, co-segregation with disease & MAF 0.00. Multifactorial likelihood analysis posterior probability >0.99 |
| Ambry Genetics | RCV000129232 | SCV000183987 | pathogenic | Hereditary cancer-predisposing syndrome | 2019-12-10 | criteria provided, single submitter | clinical testing | The p.N38H pathogenic mutation (also known as c.112A>C), located in coding exon 1 of the MLH1 gene, results from an A to C substitution at nucleotide position 112. The asparagine at codon 38 is replaced by histidine, an amino acid with similar properties. In one study, this mutation was detected in six Dutch families with HNPCC/Lynch syndrome, was associated with MSI-H tumors and inconsistent immunohistochemistry (IHC) results, and segregated with disease in all tested affected relatives. Haplotype analysis revealed that all families carried the same ancestral allele, strongly supporting p.N38H as a founder mutation of Dutch origin (van Riel E et al. Hered Cancer Clin Pract 2010; 8:7). The p.N38H mutation has been identified in patients with MSI-H Lynch syndrome-related tumors with isolated loss of PMS2 expression by IHC (van der Klift HM et al. Hum. Mutat. 2016 11;37:1162-1179). Additionally, this mutation demonstrated less than 20% of both relative mismatch repair activity and MLH1 expression in in vitro complementation assays (Drost M et al. Hum. Mutat. 2010 Mar;31:247-53; Hinrichsen I et al. Clin. Cancer Res., 2013 May;19:2432-41) and was predicted to be damaging by a methylation tolerance (MT) functional assay (Bouvet D et al. Gastroenterology, 2019 08;157:421-431). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Invitae | RCV001034681 | SCV000284006 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2019-01-11 | criteria provided, single submitter | clinical testing | Experimental studies have shown that this variant reduces the functional activity and expression of the MLH1 protein (PMID: 20020535, 23403630).  Additionally, based on a multifactorial likelihood algorithm using genetic, functional, and in silico data, this variant has been determined to have a high probability of being pathogenic (PMID: 22949379). This variant was reported in an individual with hereditary non-polyposis colon cancer (HNPCC) (PMID: 12373605) and was reported to segregate with HNPCC in 6 families (PMID: 20704743).  ClinVar contains an entry for this variant (Variation ID: 89645). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with histidine at codon 38 of the MLH1 protein (p.Asn38His). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and histidine. For these reasons, this variant has been classified as Pathogenic. |
| Myriad Genetics, |
RCV003451006 | SCV004187057 | likely pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-07-11 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 20020535, 23403630]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 20704743]. This variant is expected to disrupt protein structure [Myriad internal data]. |
| Gene |
RCV001804811 | SCV002054081 | not provided | Lynch syndrome 1 | no assertion provided | literature only |