Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
International Society for Gastrointestinal Hereditary Tumours |
RCV000075121 | SCV000106112 | pathogenic | Lynch syndrome | 2013-09-05 | reviewed by expert panel | research | Multifactorial likelihood analysis posterior probability >0.99 |
Color Diagnostics, |
RCV001176886 | SCV001340975 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2020-09-24 | criteria provided, single submitter | clinical testing | This missense variant replaces asparagine with lysine at codon 38 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Different variants affecting the same position (p.Asn38His, p.Asn38Ser, p.Asn38Thr) are considered to be disease-causing (ClinVar variation ID: 89645, 89648, 619503), suggesting that asparagine at this position is important for protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant is abnormal for complementation of mismatch repair activity in MLH1-deficient HCT116 nuclear extract (PMID: 20020535) and the expression of the variant in mouse cells resulted in DNA damage tolerance (PMID: 31784484). This variant has been reported in an individual and a family affected with Lynch syndrome-associated cancer who met Bethesda and Amsterdam I criteria (PMID: 20020535, 18415027, InSiGHT database). The variant segregates with disease in the carrier family with segregation likelihood ratio of 95:1 or LOD score of approximately 2 (InSiGHT database). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. |
Invitae | RCV001206557 | SCV001377869 | likely pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2022-08-22 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 38 of the MLH1 protein (p.Asn38Lys). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 18415027). 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 disrupts the p.Asn38 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12373605, 15713769, 20704743, 26895986, 27435373, 28514183). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects MLH1 function (PMID: 20020535, 22753075). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). ClinVar contains an entry for this variant (Variation ID: 89651). |
Ambry Genetics | RCV001176886 | SCV002617834 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2018-06-07 | criteria provided, single submitter | clinical testing | The p.N38K pathogenic mutation (also known as c.114C>G), located in coding exon 1 of the MLH1 gene, results from a C to G substitution at nucleotide position 114. The asparagine at codon 38 is replaced by lysine, an amino acid with similar properties. One in vitro assay indicated that when compared to wild type MLH1, this alteration lead to a significant decrease in mismatch repair efficiency (Drost M et al. Hum. Mutat. 2010 Mar;31:247-53). Another study found that this alteration localized to the nucleus and retained interaction with PMS2 through an in vitro GST pull-down assay (Andersen SD et al. Hum. Mutat. 2012 Dec;33:1647-55). This mutation was identified in an individual with colon cancer diagnosed at 36 whose tumor exhibited microsatellite instability and copy-neutral loss of heterozygosity (van Puijenbroek M et al. Fam. Cancer 2008 Apr;7:319-30) and was detected in a patient with colon and endometrial cancers diagnosed before age 50 where the tumor tested was MSI-H and demonstrated isolated loss of PMS2 by IHC analysis (Ambry internal data). This alteration has been classified as 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 variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
Myriad Genetics, |
RCV003451007 | SCV004189519 | likely pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-07-10 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 20020535]. This variant is expected to disrupt protein structure [Myriad internal data]. |