Submissions for variant NM_000249.4(MLH1):c.1896G>A (p.Glu632=)

dbSNP: rs63751632

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075409	SCV000106404	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Variant causes splicing aberration interrupting functional domain: full inactivation of variant allele
Invitae	RCV000524256	SCV000260588	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-09-18	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (PMID: 8571956; Invitae). ClinVar contains an entry for this variant (Variation ID: 89930). This variant has been observed in individual(s) with Lynch syndrome (PMID: 8571956, 12414824, 18625694). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 632 of the MLH1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MLH1 protein. This variant also falls at the last nucleotide of exon 16, which is part of the consensus splice site for this exon.
GeneDx	RCV000498248	SCV000589590	pathogenic	not provided	2019-09-04	criteria provided, single submitter	clinical testing	Exonic splice site variant resulting in the production of full-length transcript as well as a transcript with an in-frame deletion of exon 16 (Wijnen 1996); Not observed in large population cohorts (Lek 2016); In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12414824, 12373605, 22081473, 24278394, 25525159, 18625694, 9311737, 8571956)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000498248	SCV000889390	pathogenic	not provided	2021-06-02	criteria provided, single submitter	clinical testing	The variant is located at the last nucleotide of exon 16 and has been reported to result in aberrant RNA splicing in vitro (PMIDs: 8571956 (1996)). This variant has been reported in multiple individuals/ families affected with Lynch syndrome or colorectal cancer in the published literature (PMIDs: 8571956 (1996), 12414824 (2002), 18625694 (2008), 22081473 (2012), 24278394 (2013)). In addition, loss of MLH1 and PMS2 expression by tumor immunohistochemistry (IHC) has been reported in tumor specimens from individuals carrying this variant (PMIDs: 22081473 (2012) and 29758216 (2018)). Therefore, the variant is classified as pathogenic.
Ambry Genetics	RCV001013527	SCV001174125	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-18	criteria provided, single submitter	clinical testing	The c.1896G>A pathogenic mutation (also known as p.E632E), located in coding exon 16 of the MLH1 gene. This variant results from a G to A substitution at nucleotide position 1896. This nucleotide substitution does not change the glutamic acid at codon 632. However, this change occurs in the last base pair of coding exon 16, which makes it likely to have some effect on normal mRNA splicing. This mutation has been identified in multiple, unrelated HNPCC/Lynch syndrome families (Wijnen J et al. Am J Hum Genet. 1996 Feb;58(2):300-7; Wijnen J et al. Am J Hum Genet. 1997 Aug;61(2):329-35; Wagner A et al. J Med Genet. 2002 Nov;39(11):833-7; Ramsoekh D et al. Gut. 2008 Nov;57(11):1539-44; van Lier MG et al. J Pathol. 2012 Apr;226(5):764-74; De Lellis L et al. PLoS One. 2013 Nov 20;8(11):e81194; Ambry internal data). In addition, this variant has been identified in probands whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and loss of MLH1 and PMS2 expression by immunohistochemistry (van Lier MG et al. J Pathol. 2012 Apr;226(5):764-74; Ambry internal data). In one report, RT-PCR and protein truncation studies indicated that this alteration led to aberrant splicing resulting in skipping of exon 16 (Wijnen J et al. Am J Hum Genet. 1996 Feb;58(2):300-7). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV001013527	SCV001345310	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-01	criteria provided, single submitter	clinical testing	This synonymous variant does not change the amino acid sequence of the MLH1 protein. However, this variant causes a G to A nucleotide substitution at the last nucleotide of exon 16 of the MLH1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. A functional RNA study has shown that this variant causes skipping of exon 16 in the RNA transcript and results in truncation of the protein product (PMID: 8571956). This variant has been reported in at least 5 affected individuals from two families that have a total of ten individuals with colon cancer (PMID: 8571956, 12414824). This variant has been reported in additional individuals affected with colorectal cancer and endometrial cancer (PMID: 18625694, 22081473). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193961	SCV001363157	pathogenic	Hereditary nonpolyposis colon cancer	2019-09-30	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1896G>A (p.Glu632Glu) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. One predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Wijnen_1996). The variant was absent in 251398 control chromosomes. c.1896G>A has been reported in the literature in multiple individuals affected with Lynch Syndrome and colorectal cancer (Wijnen_1996, Wagner_2002, Ramsoekh_2008, vanLier_2012, DeLellis_2013, tenBroeke_2018). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV000605751	SCV004187357	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-24	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 8571956]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 8571956].
All of Us Research Program, National Institutes of Health	RCV000075409	SCV004843232	pathogenic	Lynch syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This synonymous variant does not change the amino acid sequence of the MLH1 protein. However, this variant causes a G to A nucleotide substitution at the last nucleotide of exon 16 of the MLH1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. A functional RNA study has shown that this variant causes skipping of exon 16 in the RNA transcript and results in truncation of the protein product (PMID: 8571956). This variant has been reported in at least 5 individuals from two families that have a total of ten individuals with colon cancer (PMID: 8571956, 12414824). This variant has been reported in additional individuals affected with colorectal cancer and endometrial cancer (PMID: 18625694, 22081473, Color internal data). 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000605751	SCV000734271	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000498248	SCV001548765	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000498248	SCV001927939	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000498248	SCV001956311	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000498248	SCV001968007	pathogenic	not provided		no assertion criteria provided	clinical testing