Submissions for variant NM_000249.4(MLH1):c.1684C>T (p.Gln562Ter)

dbSNP: rs63751460

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075313	SCV000106307	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192578	SCV001360807	pathogenic	Hereditary nonpolyposis colon cancer	2021-02-08	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1684C>T (p.Gln562X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251140 control chromosomes (gnomAD). c.1684C>T has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and related cancer phenotypes, and in some of these cases the associated tumors showed microsatellite instability (Gong_2019, Hampel_2006, Potocnik_2000). These data indicate that the variant is likely associated with disease. One publication reported experimental evidence and demonstrated that this variant also affects splicing in a minigene assay and in an in vitro splicing assay, however the overall protein level effect was not measured in this study (Rhine_2018). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV001240104	SCV001413027	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-10-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 89839). This premature translational stop signal has been observed in individual(s) with colorectal cancer (PMID: 10799973). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln562*) 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).
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001310198	SCV001499799	pathogenic	Lynch syndrome 1	2020-04-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408574	SCV002715854	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-26	criteria provided, single submitter	clinical testing	The p.Q562* pathogenic mutation (also known as c.1684C>T), located in coding exon 15 of the MLH1 gene, results from a C to T substitution at nucleotide position 1684. This changes the amino acid from a glutamine to a stop codon within coding exon 15. This mutation has been reported in multiple patients with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome (Potocnik U et al. Cancer Genet Cytogenet, 2001 Apr;126:85-96; Hampel H et al. Cancer Res, 2006 Aug;66:7810-7; Gong R et al. Cancer Manag Res, 2019 Apr;11:3721-3739). In addition to the clinical data presented in the literature, 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.	RCV003451051	SCV004186431	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-21	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.