Submissions for variant NM_000249.4(MLH1):c.1668-5T>G

dbSNP: rs1559578408

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
University of Washington Department of Laboratory Medicine, University of Washington	RCV000758579	SCV000887323	uncertain significance	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MLH1 NM_000249.3:c.1668-5T>G has a 93.2% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 26.5 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MLH1 locus. See Shirts et al 2018, PMID 29887214.
Ambry Genetics	RCV002397526	SCV002709213	uncertain significance	Hereditary cancer-predisposing syndrome	2020-09-15	criteria provided, single submitter	clinical testing	The c.1668-5T>G intronic variant results from a T to G substitution 5 nucleotides upstream from coding exon 15 in the MLH1 gene. This nucleotide position is well conserved in available vertebrate species. This alteration was identified in a tumor with loss of heterozygosity (LOH) at MLH1 locus (Shirts BH et al. Am. J. Hum. Genet., 2018 07;103:19-29). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.