Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV004036720 | SCV005033348 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-11-13 | criteria provided, single submitter | clinical testing | The c.588+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 7 of the MLH1 gene. This variant has been identified in a proband whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and 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). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient 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 likely pathogenic. |
| Department of Pathology and Laboratory Medicine, |
RCV001354775 | SCV001549470 | pathogenic | Endometrial carcinoma | no assertion criteria provided | clinical testing | The MLH1 c.588+1G>C variant was not identified in the literature nor was it identified in the dbSNP, ClinVar, GeneInsight-COGR, Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.588+1G>C variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence, and 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. An alternate substitution at this position (c.588+1G>T), however, is classified as pathogenic, reviewed by an expert panel (InSIGHT, 2013) in Clinvar. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. |