Submissions for variant NM_000249.4(MLH1):c.2092_2093del (p.Ser698fs)

dbSNP: rs63750859

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075524	SCV000106520	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
GeneDx	RCV001008104	SCV001167853	pathogenic	not provided	2018-07-06	criteria provided, single submitter	clinical testing	The c.2092_2093delTC variant in the MLH1 gene has been reported previously in association with Lynch syndrome (Mangold et al., 2005; Spaepen et al., 2006; Rossi et al., 2017). The c.2092_2093delTC variant causes a frameshift starting with codon Serine 698, changes this amino acid to an Arginine residue, and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Ser698ArgfsX5. This variant is predicted to cause loss of normal protein function through protein truncation as the last 59 amino acids are lost and replaced with 4 incorrect amino acids. The c.2092_2093delTC variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.2092_2093delTC as a pathogenic variant.
Invitae	RCV001380412	SCV001578477	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-04-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser698Argfs*5) in the MLH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 59 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 clinical features of Lynch syndrome (PMID: 15849733, 16736289, 20305446, 31139268). ClinVar contains an entry for this variant (Variation ID: 90039). 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.
Ambry Genetics	RCV002415538	SCV002725040	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-14	criteria provided, single submitter	clinical testing	The c.2092_2093delTC pathogenic mutation, located in coding exon 18 of the MLH1 gene, results from a deletion of two nucleotides at nucleotide positions 2092 to 2093, causing a translational frameshift with a predicted alternate stop codon (p.S698Rfs*5). This alteration occurs at the 3' terminus of MLH1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 59 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This mutation has been reported in multiple families with HNPCC/Lynch syndrome (Liu B et al. Nat. Med. 1996 Feb;2:169-74; Coleman MG et al. Br. J. Cancer. 2001 Nov;85:1486-91; Mangold E et al. Int. J. Cancer, 2005 Sep;116:692-702; Spaepen M et al. Fam. Cancer, 2006;5:179-89; Rossi BM et al. BMC Cancer, 2017 Sep;17:623; Jiang W et al. Hered Cancer Clin Pract, 2019 May;17:13). Of note, this alteration is also designated as c.2089_ 2090delCT in the published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003455996	SCV004186470	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.