Submissions for variant NM_000249.4(MLH1):c.1024_1038+1del

dbSNP: rs1553648201

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586802	SCV000696090	pathogenic	Lynch syndrome	2016-11-21	criteria provided, single submitter	clinical testing	Variant summary: The MLH1 c.1024_1038+1delATGTACTTCACCCAGG variant involves the deletion of 16 nucleotides around the exon/intron 11 border. Mutation taster predicts a damaging outcome for this substitution while 5/5 splice site tools predicts the variant to create a splice site at nucleotide 1023. The aberrant splicing product is predicted to result in an in-frame deletion p.Met342_Gln346del deletion (Alamut). This variant is absent in 120030 control chromosomes. It was reported in multiple LS patients (Pino_2009, Cruz-Correa_2015) and at least one family, it was shown to co-segregate with the disease in two affected family members, strongly supporting for causality. Taken together, this variant is classified as pathogenic.
Invitae	RCV000791474	SCV000930725	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (Splice site) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. 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). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 19324997, 25782445; Invitae). This variant is also known as c.1024del16 and c.1024_1038+1del. ClinVar contains an entry for this variant (Variation ID: 495757). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001017049	SCV001178072	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-01-30	criteria provided, single submitter	clinical testing	The c.1024_1038+1del16 variant results from a deletion of 16 nucleotides between positions 1024 and 1038+1 and involves the canonical splice donor site after coding exon 11 of the MLH1 gene. This variant has been identified in a proband(s) who met Amsterdam I/II criteria for Lynch syndrome; however, immunohistochemistry and microsatellite instability results from these tumors were not always consistent with MLH1-related disease (Pino MS et al. J Mol Diagn. 2009 May;11(3):238-47; Cruz-Correa M et al. Fam. Cancer. 2015 Sep;14(3):415-25; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This canonical splice donor site is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. 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. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001017049	SCV001356162	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-16	criteria provided, single submitter	clinical testing	This variant deletes 16 nucleotides in exon 11 of the MLH1 gene, predicted to create a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. 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.
Myriad Genetics, Inc.	RCV003451328	SCV004186361	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-19	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.