Submissions for variant NM_000249.4(MLH1):c.1210_1211del (p.Leu404fs)

dbSNP: rs63751015

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075150	SCV000106141	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Color Diagnostics, LLC DBA Color Health	RCV000579501	SCV000684729	pathogenic	Hereditary cancer-predisposing syndrome	2020-04-28	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 12 of the MLH1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch Syndrome (PMID: 16830052, 18618713). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000075150	SCV000696099	pathogenic	Lynch syndrome	2016-03-01	criteria provided, single submitter	clinical testing	Variant summary: The c.1210_1211delCT variant results in a premature termination codon, predicted to cause a truncated or absent MLH1 protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1489dupC, c.1772_1775delATAG). One in-silico tool predicts damaging outcome for this variant. This variant is not found in 121406 control chromosomes, however, it has been reported in at least 3 LS patients. In addition, one reputable database classified this variant as pathogenic. Taken together, this variant was classified as pathogenic.
Invitae	RCV000698961	SCV000827652	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu404Valfs*12) 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 Lynch syndrome-related endometrial cancer and colorectal cancer (PMID: 16830052, 18618713, 18772310). ClinVar contains an entry for this variant (Variation ID: 89678). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759080	SCV000888174	pathogenic	not provided	2023-01-30	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the MLH1 mRNA and causes the premature termination of MLH1 protein synthesis. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with colorectal cancer (PMID: 29596542 (2018)) and Lynch syndrome (PMIDs: 29360161 (2018), 28529006 (2017), 18618713 (2008), 16830052 (2006)). Based on the available information, this variant is classified as pathogenic.
Ambry Genetics	RCV000579501	SCV001170537	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-13	criteria provided, single submitter	clinical testing	The c.1210_1211delCT pathogenic mutation, located in coding exon 12 of the MLH1 gene, results from a deletion of two nucleotides at nucleotide positions 1210 to 1211, causing a translational frameshift with a predicted alternate stop codon (p.L404Vfs*12). This pathogenic mutation has been reported in several families meeting Amsterdam I criteria where multiple individuals had MSI-high tumors exhibiting absent MLH1 staining on IHC (Zavodna K et al. Neoplasma 2006; 53(4):269-76; Bujalkova M et al. Clin. Chem. 2008 Nov;54(11):1844-54; Alemayehu A et al. Genes Chromosomes Cancer 2008 Oct;47(10):906-14; Dudley B et al. Cancer, 2018 Apr;124:1691-1700; Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003451012	SCV004186325	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-19	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.