Submissions for variant NM_000249.4(MLH1):c.1039-1G>A

dbSNP: rs267607819

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075088	SCV000106082	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Variant causes splicing aberration (not quantified), 2 MSI-H tumours, segregation with disease & absent in 1000 genomes
GeneDx	RCV000153506	SCV000211092	pathogenic	not provided	2019-06-05	criteria provided, single submitter	clinical testing	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)
Eurofins Ntd Llc (ga)	RCV000153506	SCV000700694	pathogenic	not provided	2014-02-24	criteria provided, single submitter	clinical testing
Invitae	RCV001201713	SCV001372799	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-19	criteria provided, single submitter	clinical testing	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.
Revvity Omics, Revvity	RCV000153506	SCV002017498	pathogenic	not provided	2019-08-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000153506	SCV002563756	pathogenic	not provided	2021-07-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390213	SCV002697954	pathogenic	Hereditary cancer-predisposing syndrome	2018-08-20	criteria provided, single submitter	clinical testing	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.
Myriad Genetics, Inc.	RCV003451000	SCV004185905	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-19	criteria provided, single submitter	clinical testing	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000075088	SCV004848302	pathogenic	Lynch syndrome	2019-10-14	criteria provided, single submitter	clinical testing	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.