Submissions for variant NM_000249.4(MLH1):c.1558+1G>A

dbSNP: rs267607832

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000204627	SCV000260539	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-05-23	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site is associated with altered splicing resulting in unknown protein product impact (Invitae). ClinVar contains an entry for this variant (Variation ID: 220185). Disruption of this splice site has been observed in individuals with Lynch syndrome (PMID: 15178966, 21286823). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 13 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).
Ambry Genetics	RCV000223493	SCV000274273	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-28	criteria provided, single submitter	clinical testing	The c.1558+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 13 of the MLH1 gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration has been identified in individuals with a family history that met Amsterdam criteria for Lynch syndrome and/or showed high microsatellite instability (MSI-H) or loss of PMS2 protein expression by immunohistochemistry in their colorectal tumors (Ambry internal data). This variant was identified in 1/111 Japanese patients meeting Amsterdam criteria and was reported in a Chinese proband diagnosed with diffuse gastric cancer and colorectal cancer at the age of 77 (Ikenoue T et al. J Hum Genet, 2019 Dec;64:1187-1194; Aronson M et al. Curr Oncol, 2020 04;27:e182-e190). This variant was also identified in a proband diagnosed with early-onset MSI-H colorectal cancer and RT-PCR analysis demonstrated an insertion of 108 nucleotides from intron 13 was associated with this variant (Morak M et al. Eur J Hum Genet, 2019 12;27:1808-1820). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in a splice defect; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). In addition to the clinical data reported 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	RCV000781542	SCV000919662	likely pathogenic	Lynch syndrome	2018-09-27	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1558+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 246094 control chromosomes (gnomAD). The variant, c.1558+1G>A, has been reported in the literature in at least one individual affected with Lynch Syndrome (Ishida_2018), and variants at the same nucleotide position (c.1558+1G>T, c.1558+1G>C) have been associated with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and both classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV001507621	SCV001713277	likely pathogenic	not provided	2019-08-08	criteria provided, single submitter	clinical testing	PVS1, PM2
Myriad Genetics, Inc.	RCV003454544	SCV004189408	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-20	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.