Submissions for variant NM_000249.4(MLH1):c.2065C>T (p.Gln689Ter)

dbSNP: rs41542214

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160542	SCV000211119	pathogenic	not provided	2014-07-01	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted MLH1 c.2065C>T at the cDNA level and p.Gln689Ter (Q689X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through protein truncation. Although this variant has not, to our knowledge, been reported in the literature, it is considered pathogenic.
Invitae	RCV000531300	SCV000625119	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-08-20	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln689*) in the MLH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 68 amino acid(s) of the MLH1 protein. This premature translational stop signal has been observed in individual(s) with breast and colon cancer (PMID: 26681312). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MLH1 protein in which other variant(s) (c.2269dup and c.2266_2269dup) have been determined to be pathogenic (PMID: 8128251, 9697702, 12810663, 14985405). 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: 182529).
Mendelics	RCV000708931	SCV000838029	pathogenic	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415704	SCV002727653	pathogenic	Hereditary cancer-predisposing syndrome	2019-09-30	criteria provided, single submitter	clinical testing	The p.Q689* pathogenic mutation (also known as c.2065C>T), located in coding exon 18 of the MLH1 gene, results from a C to T substitution at nucleotide position 2065. This changes the amino acid from a glutamine to a stop codon within coding exon 18. 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.
Myriad Genetics, Inc.	RCV003453267	SCV004189871	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.