Submissions for variant NM_000249.4(MLH1):c.2190del (p.Pro731fs)

dbSNP: rs587780683

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122975	SCV000166251	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-10-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro731Leufs*52) in the MLH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 26 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: 22480969, 24733792). ClinVar contains an entry for this variant (Variation ID: 135851). 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.Tyr750*, p.Lys751Serfs*3) have been determined to be pathogenic (PMID: 8797773, 12799449, 16338176, 18566915, 20533529, 24802709, 27295708; 18931482andinternal datadatabase). 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.	RCV003453054	SCV004189901	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 the incorporation of abnormal amino acid sequence into the protein product and abnormal protein elongation.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356466	SCV001551643	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MLH1 p.Pro731LeufsX52 variant was identified in 5 of 548 proband chromosomes (frequency: 0.01) from individuals or families with breast cancer and Lynch Syndrome (Kurian 2014, Rouleau 2009). The variant was also identified in dbSNP (ID: rs587780683) as “with Pathogenic allele”, and in ClinVar as pathogenic by Invitae. The variant was further identified in the UMD-LSDB database 5X and listed as casual. The variant was not identified in the COGR, Cosmic, MutDB, Insight Colon Cancer Gene Variant databse, Zhejiang University database, Mismatch Repair Genes Variant database, and Insight Hereditary Tumors database. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, and the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.2190del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 731 and leads to a premature stop codon at position 782. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MLH1 gene are an established mechanism of disease in Lynch Syndrome and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.