Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000410339 | SCV000489029 | likely pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2016-08-05 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000684811 | SCV000543566 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2023-02-11 | criteria provided, single submitter | clinical testing | This sequence change affects an acceptor splice site in intron 5 of the MLH1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Lynch syndrome (PMID: 8940269, 12658575). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS5-1G>C. ClinVar contains an entry for this variant (Variation ID: 371909). 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 | RCV000568411 | SCV000676057 | pathogenic | Hereditary cancer-predisposing syndrome | 2019-12-09 | criteria provided, single submitter | clinical testing | The c.454-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 6 of the MLH1 gene. This variant has been identified in a proband(s) who met Amsterdam I/II criteria for Lynch syndrome (Ambry internal data; Wagner A et al. Am J Hum Genet, 2003 May;72:1088-100). This variant has also been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated loss of MLH1/PMS2 expression by immunohistochemistry (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in an incomplete splice defect involving exons excluded from naturally occurring transcripts; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000472090 | SCV000696167 | likely pathogenic | Lynch syndrome | 2016-04-11 | criteria provided, single submitter | clinical testing | Variant summary: The MLH1 c.454-1G>C variant affects a conserved intronic nucleotide at the invariant AG acceptor splice site of intron 5. Mutation Taster predicts damaging outcome for this variant, and 4/5 Alamut algorithms predict elimination of the splice acceptor site; however, the variant has not been evaluated for functional impact by in vivo/vitro studies. This variant was not found in 120912 control chromosomes, but has been cited in 1 HNPCC family (Wagner_AJHG_2003); and a similar variant, c.454-1G>A, has been cited in HNPCC patients from multiple families and has been classified as pathogenic. Additionally, frameshift, splice-site, and nonsense variants downstream of this variant have been classified as pathogenic (i.e. p.Arg487X, p.Asp591fsX24, c.1731G>A, etc). Taken together, this variant was classified as likely pathogenic until additional information is available. |