Submissions for variant NM_000249.4(MLH1):c.2194A>T (p.Lys732Ter)

dbSNP: rs267607906

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075573	SCV000106570	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon within functional domain in last exon
Invitae	RCV000558933	SCV000625133	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-10-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MLH1 protein in which other variant(s) (p.Tyr750*, p.Lys751Serfs*3) have been determined to be pathogenic (PMID: 8797773, 12799449, 16338176, 18566915, 20533529, 24802709, 27295708; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 90087). This premature translational stop signal has been observed in individual(s) with Muir-Torre syndrome and Lynch syndrome (PMID: 10923051, 25197397). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys732*) in the MLH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 25 amino acid(s) of the MLH1 protein.
Ambry Genetics	RCV000564805	SCV000676048	pathogenic	Hereditary cancer-predisposing syndrome	2020-09-03	criteria provided, single submitter	clinical testing	The p.K732* pathogenic mutation (also known as c.2194A>T), located in coding exon 19 of the MLH1 gene, results from an A to T substitution at nucleotide position 2194. This changes the amino acid from a lysine to a stop codon within coding exon 19. This alteration occurs at the 3' terminus of theMLH1 gene and is not expected to trigger nonsense-mediated mRNA decay and only impacts the last 25 amino acids of the protein; however, premature stop codons are typically deleterious in nature. This mutation has been previously reported in a woman of Czech ancestry who was diagnosed with colorectal cancer at age 37 and reportedly met Amsterdam criteria as well as a Caucasian women with endometrial cancer at age 31 with corresponding immunohistochemical (IHC) testing (Hajer J et al. Hum. Mutat. 2000 Aug;16(2):181; Latham A et al. J. Clin. Oncol., 2019 02;37:286-295). This mutation has also been observed in a Caucasian woman with a diagnosis of Muir-Torre syndrome due to metachronous colorectal, endometrial, gastric, and sebaceous carcinomas, all of which showed absence of MLH1 protein expression by IHC analysis (Svec J et al. Int J Clin Exp Pathol. 2014 Jul;7(8):5196-202). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003451115	SCV004186433	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 termination codon and is predicted to result in premature protein truncation.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353662	SCV000592445	uncertain significance	not provided		no assertion criteria provided	clinical testing