Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000075529 | SCV000106526 | pathogenic | Lynch syndrome | 2013-09-05 | reviewed by expert panel | research | Multifactorial likelihood analysis posterior probability >0.99 |
| Invitae | RCV001380413 | SCV001578478 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2023-08-18 | criteria provided, single submitter | clinical testing | This variant disrupts a region of the MLH1 protein in which other variant(s) (p.Trp714*) have been determined to be pathogenic (PMID: 8863153, 9697702, 12799449, 12810663, 16338176, 17510385, 20533529). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This sequence change affects a donor splice site in intron 18 of the MLH1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with MLH1-related conditions (PMID: 8571956, 15342696, 22883484, 27247567, 28195393). ClinVar contains an entry for this variant (Variation ID: 90044). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002415541 | SCV002724565 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-09-26 | criteria provided, single submitter | clinical testing | The c.2103+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 18 of the MLH1 gene. This pathogenic mutation has been reported in numerous individuals/families with Lynch syndrome, many of whom had tumor studies showing absent MLH1 protein expression on immunohistochemistry (IHC) (Wijnen J et al. Am. J. Hum. Genet. 1996 Feb;58(2):300-7; Berends MJ et al. Int. J. Cancer. 2001 May;92(3):398-403; Wagner A et al. Am. J. Hum. Genet. 2003 May;72(5):1088-100; Overbeek LI et al. Br. J. Cancer. 2007 May;96(10):1605-12; Bonadona V et al. JAMA, 2011 Jun;305:2304-10; Skeldon SC et al. Eur. Urol. 2013 Feb;63(2):379-85; Lagerstedt-Robinson K et al. Oncol. Rep. 2016 Nov;36:2823-2835). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing. As such, this alteration is classified as a disease-causing mutation. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000202158 | SCV004220870 | pathogenic | not provided | 2023-05-26 | criteria provided, single submitter | clinical testing | The MLH1 c.2103+1G>A variant disrupts a canonical splice-donor site and interferes with normal MLH1 mRNA splicing. This variant has been reported in the published literature in In the published literature, this variant has been reported in individuals and families with Lynch Syndrome and Lynch-related cancers (PMIDs: 29758216 (2018), 27601186 (2016), 22883484 (2013), 21642682 (2011), 17453009 (2007), 12658575 (2003), 12547705 (2003), 11291077 (2001), 8571956 (1996)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. |
| Mayo Clinic Laboratories, |
RCV000202158 | SCV000257085 | pathogenic | not provided | no assertion criteria provided | research | ||
| Department of Pathology and Laboratory Medicine, |
RCV000202158 | SCV000592440 | uncertain significance | not provided | no assertion criteria provided | clinical testing |