Submissions for variant NM_000249.4(MLH1):c.790+1G>A

dbSNP: rs267607789

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075847	SCV000106862	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Variant causes splicing aberration interrupting protein function: full inactivation of variant allele
GeneDx	RCV000214767	SCV000279403	pathogenic	not provided	2023-06-05	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Identified in individuals with MLH1-related cancers with concordant immunohistochemistry in published literature (Cummingham et al., 2001; Ward et al., 2002; Casey et al., 2005; Sanchez de Abajo et al., 2006; Ewald et al., 2007; Sheng et al., 2009; Alvarez et al., 2010; Haraldsdottir et al., 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15200905, 15849733, 17440950, 16142001, 12200596, 15289847, 18692554, 18726168, 16341804, 18713544, 16276679, 12658575, 25525159, 25107687, 25133505, 25338684, 32549215, 31830689, 32294063, 17054581, 19248199, 16288214, 15955785, 20587412, 20937110, 15872200, 15713769, 9057658, 11524701, 26895986, 28874130, 28248820, 26666765, 20305446, 29887214, 30093976, 34178123, 32490589, 30787465, 16395668)
Invitae	RCV000524316	SCV000284075	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 9 of the MLH1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Lynch syndrome and colorectal cancer (PMID: 11524701, 15849733, 15955785, 17054581, 20937110, 24710284). This variant is also known as IVS9+1G>A. ClinVar contains an entry for this variant (Variation ID: 90356). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects MLH1 function (PMID: 11781295). Studies have shown that disruption of this splice site results in skipping of exons 9-10, but is expected to preserve the integrity of the reading-frame (PMID: 16395668). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000214767	SCV000601410	pathogenic	not provided	2023-02-01	criteria provided, single submitter	clinical testing	The MLH1 c.790+1G>A variant (also known as IVS9+1G>A) disrupts a canonical splice site and has been shown to cause an in-frame skipping of exons 9-10 (PMID: 16395668 (2006)), at a level greater the alternatively spliced isoforms observed in normal cells (PMIDs: 9490293 (1998), 7728749 (1995)). The frequency of this variant in the general population, 0.0000066 (1/152090 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. The variant has been reported in multiple individuals with colorectal cancer or Lynch syndrome (PMIDs: 26895986 (2016), 25133505 (2014), 25107687 (2014), 24344984 (2013), 20937110 (2010), 20305446 (2010), 17054581 (2006), 16395668 (2006), 15955785 (2005), 15849733 (2005), 11524701 (2001)). A functional study also indicates the variant causes a significant loss of DNA mismatch repair activity (PMID: 11781295 (2002)). Based on the available information, this variant is classified as pathogenic.
Ambry Genetics	RCV000562275	SCV000664831	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-14	criteria provided, single submitter	clinical testing	The c.790+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 9 of the MLH1 gene. This mutation has been seen in multiple individuals with personal and family histories of colon cancer (Cunningham JM et al. Am. J. Hum. Genet. 2001 Oct;69:780-90; Rosty C et al. BMJ Open. 2016 Feb;6(2):e010293; Haraldsdottir S et al. Fam. Cancer 2016 Apr;15(2):253-60; Rossi BM et al. BMC Cancer 2017 Sep;17(1):623). In addition, a functional study utilizing RNA from an individual carrying this mutation found that it leads to skipping of coding exons 9 and 10 (Auclair J et al. Hum. Mutat. 2006 Feb;27:145-54; Ambry internal data). 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 a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000075847	SCV000696180	pathogenic	Lynch syndrome	2016-11-15	criteria provided, single submitter	clinical testing	Variant summary: The MLH1 c.790+1G>A variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict that this variant ablishes the 5' splicing donor site, which was confirmed by an in vitro study (Auclair_2006). This variant has been found in numerous LS patients and is absent in 115338 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000562275	SCV000905468	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-14	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 9 splice donor site of the MLH1 gene. Functional RNA studies have shown that this variant causes a skipping of exons 9 and 10 (PMID: 16395668, 20937110) at a level far greater than the low-level alternate splicing reported in normal cells (PMID: 7728749, 9490293). This alternate splicing results in the deletion of amino acids 227-295 and loss of mismatch repair activity of the MLH1 protein (PMID: 11781295). This variant has been reported in individuals affected with Lynch syndrome (PMID: 15955785, 16395668, 19248199, 20937110, 25107687, 26666765, 26895986, 28874130) and colorectal cancer (PMID: 11524701,15713769). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001310196	SCV001499797	pathogenic	Lynch syndrome 1	2020-04-02	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000214767	SCV002009354	likely pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000214767	SCV002552439	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003452766	SCV004190062	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-17	criteria provided, single submitter	clinical testing	This variant is considered 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. Functional studies indicate this variant impacts protein function [PMID: 8574961, 11781295].
Baylor Genetics	RCV003452766	SCV004193027	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2022-12-19	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000214767	SCV000592374	pathogenic	not provided		no assertion criteria provided	clinical testing
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001249934	SCV001423876	pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001646997	SCV001860284	pathogenic	Colonic neoplasm	2021-09-12	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000214767	SCV001951623	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000214767	SCV001964056	pathogenic	not provided		no assertion criteria provided	clinical testing
CZECANCA consortium	RCV003128140	SCV003804325	pathogenic	Endometrial carcinoma	2023-02-21	no assertion criteria provided	clinical testing