Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000075875 | SCV000106890 | pathogenic | Lynch syndrome | 2013-09-05 | reviewed by expert panel | research | Coding sequence variation resulting in a stop codon |
| Invitae | RCV000704907 | SCV000833880 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2018-05-15 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Ser269*) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals and families affected with Lynch syndrome (PMID: 15571801, 12547705, 18625694, 17453009, 9311737). ClinVar contains an entry for this variant (Variation ID: 17098). Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002408469 | SCV002675923 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-07-13 | criteria provided, single submitter | clinical testing | The p.S269* pathogenic mutation (also known as c.806C>G), located in coding exon 10 of the MLH1 gene, results from a C to G substitution at nucleotide position 806. This changes the amino acid from a serine to a stop codon within coding exon 10. This mutation has been identified in multiple individuals diagnosed with HNPCC/Lynch syndrome (Wijnen J et al. Am. J. Hum. Genet. 1997 Aug;61:329-35; Hendriks Y et al. Am. J. Pathol. 2003 Feb;162:469-77; Overbeek LI et al. Br. J. Cancer 2007 May;96:1605-12), including several patients whose tumors demonstrated high microsatellite instability and loss of MLH1 staining on immunohistochemistry (IHC) (van Puijenbroek M et al. Fam. Cancer 2008 Apr;7:319-30; Bosse T et al. Mod Pathol, 2013 Nov;26:1525-35; Post CCB et al. J Natl Cancer Inst, 2021 Mar). This mutation has also been reported as homozygous in a patient with colon cancer diagnosed at age 22 (Rey JM et al. Cancer Genet Cytogenet, 2004 Dec;155:149-51). Of note, this alteration is also designated as 269 TCA>TGA, S269X, and p.Ser269X in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. |
| OMIM | RCV000018631 | SCV000038914 | pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2004-12-01 | no assertion criteria provided | literature only | |
| 3DMed Clinical Laboratory Inc | RCV000677880 | SCV000804041 | pathogenic | Colon cancer | 2018-02-10 | no assertion criteria provided | clinical testing | |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV001723579 | SCV001957887 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV001723579 | SCV001969706 | pathogenic | not provided | no assertion criteria provided | clinical testing |