Submissions for variant NM_000249.4(MLH1):c.1410-2_1410-1delinsCC

dbSNP: rs1559558071

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000709740	SCV000840009	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2017-07-05	criteria provided, single submitter	clinical testing	This c.1410-2_1410-1delinsCC variant has not been reported in public databases, nor been observed in our patient cohort. However, both c.1410-1G>C and c.1410-2A>C changes have been reported in an individual from Africa in the ExAC population database each (http://exac.broadinstitute.org/variant/3-37070274-G-C, http://exac.broadinstitute.org/variant/3-37070273-A-C) and may represent the same variant in one single individual from this population. This variant affects the invariant acceptor splice site of intron 12. While not validated for clinical use, computer-based algorithms SIFT and Polyphen-2 predict this variant to activate a cryptic splice site within exon 12 at position c.1414_1415GA, which would result in the disruption of the reading frame and a premature stop codon. This variant is thus predicted to result in a loss of function of the MLH1 protein. It is thus interpreted as a pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780421	SCV000917663	likely pathogenic	Lynch syndrome	2018-08-28	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1410-2_1410-1delinsCC alters two nucleotides 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: Four predict the variant abolishes a 3' acceptor site and three predict the variant creates a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.1e-06 in 246200 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1410-2_1410-1delinsCC in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV001011400	SCV001171716	pathogenic	Hereditary cancer-predisposing syndrome	2019-02-25	criteria provided, single submitter	clinical testing	The c.1410-2_1410-1delAGinsCC intronic pathogenic mutation results from a deletion of AG and the insertion of CC two nucleotides upstream from coding exon 13 of the MLH1 gene. This alteration has been detected in an individual diagnosed with colon cancer whose tumor showed absence of MLH1 and PMS2 protein on IHC (Ambry internal data). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In addition, alterations that disrupt the canonical splice acceptor 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	RCV001247047	SCV001420445	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-10-15	criteria provided, single submitter	clinical testing	This sequence change affects a 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). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 585224). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Myriad Genetics, Inc.	RCV000709740	SCV004187068	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000780421	SCV004847967	pathogenic	Lynch syndrome	2016-02-16	criteria provided, single submitter	clinical testing	The c.1410-2_1410-1delinsCC variant in MLH1 has not been previously reported in individuals with Lynch syndrome or in large population studies. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In summary, this variant meets our criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner based on the predicted impact of the variant.