ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1558+1G>A (rs267607832)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204627 SCV000260539 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-08-24 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 13 of the MLH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in several individuals affected with Lynch syndrome (PMID: 15178966, 21286823). This splice site has also been reported as IVS13+1G in the literature. ClinVar contains an entry for this variant (Variation ID: 220185). Donor and acceptor splice site variants 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). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000223493 SCV000274273 pathogenic Hereditary cancer-predisposing syndrome 2019-03-12 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 alteration has been identified in individuals with a family history that met Amsterdam criteria for Lynch syndrome and/or showed loss of PMS2 protein expression by immunohistochemistry in their colorectal tumors (Ambry internal data). Another alteration at the same position, c.1558+1G>T, was identified in an Italian man whose family history met Amsterdam I criteria and his small bowel tumor showed high microsatellite instability (MSI-H). Functional studies using reverse transcriptase polymerase chain reaction (RT-PCR) revealed aberrant splicing in this patient due to the use of a cryptic splice site (Benatti P et al. Am. J. Gastroenterol., 1998 Nov;93:2219-22). 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 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

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