Submissions for variant NM_000249.4(MLH1):c.1409+1G>A

dbSNP: rs267607825

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075192	SCV000106182	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Ambry Genetics	RCV000220831	SCV000276156	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-14	criteria provided, single submitter	clinical testing	The c.1409+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 12 of the MLH1 gene. This variant has been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated loss of MLH1/PMS2 expression by immunohistochemistry (Ambry internal data). This mutation has also been described in a Latvian individual with suspected HNPCC (Irmejs A et al. Anticancer Res. 2007;27(1):653-8). In addition, another mutation at the same nucleotide position, c.1409+1G>C, has been described in a Baltic/Polish individual fulfilling Amsterdam II criteria for HNPCC (Kurzawski G et al. J Med Genet. 2002;39:e65). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor 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 a disease-causing mutation.
Invitae	RCV000524237	SCV000543606	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-07-26	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 12 of the MLH1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Lynch syndrome (PMID: 17348456). ClinVar contains an entry for this variant (Variation ID: 89718). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.1409+1G nucleotide in the MLH1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 9322509, 10200055, 12362047, 14574010, 16451135). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000519388	SCV000617551	pathogenic	not provided	2017-07-20	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.1409+1G>A or IVS12+1G>A and consists of a G>A nucleotidesubstitution at the +1 position of intron 12 of the MLH1 gene. This variant destroys a canonical splice donor site and ispredicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported in at least one family withuterine and colorectal cancer (Irmejs 2007) and an alternate change, MLH1 c.1409+1G>C, has been observed in atleast one family meeting Amsterdam Criteria for Lynch syndrome (Peltomäki 1997, Kurzawski 2002). Based on thecurrent evidence, we consider MLH1 c.1409+1G>A to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000075192	SCV000696109	likely pathogenic	Lynch syndrome	2017-07-12	criteria provided, single submitter	clinical testing	Variant summary: The MLH1 c.1409+1G>A variant involves the alteration of a non-conserved intronic nucleotide that 5/5 splice prediction tools predict a the elimination of a canonical 5' splice donor site. However, these predictions have yet to be confirmed by functional studies. This variant is absent in 120470 control chromosomes. A publication cites the variant in an affected individual. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic. Taken together, this variant is classified as likely pathogenic.
GeneKor MSA	RCV000519388	SCV000821733	likely pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing	This variant is a substitution of the first nucleotide of intron 12 of the MLH1 gene. This position is highly conserved in human and other genomes. It is expected that this variant affects the correct mRNA splicing and results in the deletion of an entire exon. This causes the formation of a truncated non functional protein. This mutation has been described in international literature in families with suspected Lynch syndrome (PMID: 17348456).
Color Diagnostics, LLC DBA Color Health	RCV000220831	SCV002053606	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-03-04	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the canonical +1 position of intron 12 splice donor site of the MLH1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although RNA studies have not been reported, this variant is expected to impair splicing and result in an absent or non-functional protein product. This variant has been reported in an individual affected with colorectal cancer with uterine cancer in the first-degree relative (PMID: 17348456). 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 Likely Pathogenic.
Myriad Genetics, Inc.	RCV003451024	SCV004186376	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-20	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. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726].
Baylor Genetics	RCV003451024	SCV004193034	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2022-10-06	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000075192	SCV004848304	pathogenic	Lynch syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The c.1409+1G>A variant in MLH1 has been previously reported in 1 individual suspected to have Lynch syndrome (Irmejs 2007) and was absent from large population studies. This variant was classified as Pathogenic by several clinical labs in ClinVar and as Likely pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 89718). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Other variants involving this position (c.1409+1G>C, c.1409+1G>T) have been classified as likely pathogenic/Pathogenic in ClinVar. Heterozygous loss-of-function of the MLH1 gene is an established disease mechanism in individuals with Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP criteria applied: PVS1, PM2, PM5.