Submissions for variant NM_000249.4(MLH1):c.2104-1G>A

dbSNP: rs587778978

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
University of Washington Department of Laboratory Medicine, University of Washington	RCV000758582	SCV000887329	pathogenic	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MLH1 NM_000249.3:c.2104-1G>A has a 99.9% 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.
Invitae	RCV001211814	SCV001383373	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-10-28	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site is associated with altered splicing resulting in exon 19 skipping (PMID: 24362816). ClinVar contains an entry for this variant (Variation ID: 619515). This variant is also known as IVS18-1G>A. Disruption of this splice site has been observed in individual(s) with colorectal or ovarian cancer (PMID: 8592341, 14635101). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency).
Ambry Genetics	RCV002422640	SCV002725907	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-04-15	criteria provided, single submitter	clinical testing	The c.2104-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 19 of the MLH1 gene. This nucleotide position is highly conserved in available vertebrate species. This alteration, designated c.IVS18-1G>A, was identified in a cohort of colorectal cancer patients from the UK (Taylor CF et al. Hum. Mutat. 2003 Dec;22(6):428-33). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. In addition to the clinical data presented in the literature, 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.
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001249940	SCV001423882	pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing