ClinVar Genomic variation as it relates to human health

Variant causes splicing aberration (not quantified), 2 MSI-H tumours, segregation with disease & absent in 1000 genomes

Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); Reported as pathogenic in ClinVar but additional evidence is not available; This variant is associated with the following publications: (PMID: 11306449, 11854177, 10200055, 26681312, 9322509, 11507050, 14574010, 23716351, 10793088, 29296220)

This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.

The c.1039-1G>A variant in MLH1 has been reported in at least 1 individual with Lynch syndrome (Peltomaki 1997), 1 individual with history of colon cancer and sarcoma (Susswein 2016), and 1 individual with endometrioid cancer (Niskakoski 2013). It was absent from large population studies. This variant was classified as Pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 89619). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the MLH1 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting.

The c.1039-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 12 of the MLH1 gene. This mutation is expected to cause an out-of-frame deletion of exon 12 and has been reported in multiple Finnish individuals with colorectal cancer and family histories of HNPCC-associated cancers (Peltomäki P et al. Gastroenterology 1997 Oct;113:1146-58; Holmberg M et al. Hum. Mutat. 1998;11:482; Kuismanen SA et al. Am. J. Pathol. 2000 May;156:1773-9; Bala S et al. Cancer Res. 2001 Aug;61:6042-5; Peltomäki P et al. Fam. Cancer 2001;1:9-15). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. 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 pathogenic.

This sequence change affects an acceptor splice site in intron 11 of the MLH1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with clinical features of Lynch Syndrome (PMID: 9322509, 19669161, 26681312, 28944238; Invitae). ClinVar contains an entry for this variant (Variation ID: 89619). Studies have shown that disruption of this splice site results in skipping of exon 12 and introduces a premature termination codon (PMID: 19669161; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.