Submissions for variant NM_000249.4(MLH1):c.2181_2182del (p.Ile728fs)

dbSNP: rs267607898

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075570	SCV000106567	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon with functional domain
Ambry Genetics	RCV000569577	SCV000676309	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-14	criteria provided, single submitter	clinical testing	The c.2181_2182delCA pathogenic mutation, located in coding exon 19 of the MLH1 gene, results from a deletion of two nucleotides at nucleotide positions 2181 to 2182, causing a translational frameshift with a predicted alternate stop codon (p.I728Sfs*4). This mutation (designated as"a 2-bp deletion at codon 726") has been reported in a family meeting Amsterdam criteria (Mauillon JL et al. Cancer Res. 1996 Dec;56:5728-33). This variant has also been reported in an individual diagnosed with MLH1 deficient colorectal cancer at age 29 (Kang SY et al. Int J Cancer, 2015 Apr;136:1568-78). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV001233676	SCV001406281	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile728Serfs*4) in the MLH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acid(s) of the MLH1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 8971183). This variant is also known as a deletion of CA at codons 726-728. ClinVar contains an entry for this variant (Variation ID: 90084). 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 a region of the MLH1 protein in which other variant(s) (p.Lys751Serfs*3) have been determined to be pathogenic (PMID: 8797773, 18566915, 18931482, 24802709, 27295708). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV003451114	SCV004186567	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-25	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.