Submissions for variant NM_000249.4(MLH1):c.256C>T (p.Gln86Ter)

dbSNP: rs63751421

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075607	SCV000106604	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding variation resulting in premature termination codon
Ambry Genetics	RCV002453384	SCV002738884	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-18	criteria provided, single submitter	clinical testing	The p.Q86* pathogenic mutation (also known as c.256C>T), located in coding exon 3 of the MLH1 gene, results from a C to T substitution at nucleotide position 256. This changes the amino acid from a glutamine to a stop codon within coding exon 3. This mutation has been reported in Polish, Hispanic, and Chinese patients with Lynch syndrome (Kurzawski G et al. Clin. Genet. 2006 Jan;69:40-7; Sunga AY et al. Cancer Genet, 2017 Apr;212-213:1-7; Tian W et al. Int J Cancer, 2019 09;145:1290-1298). Of note, this alteration is also designated as Q86X and p.Gln86Ter in published literature. 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.
Invitae	RCV002513802	SCV003525126	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-02-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln86*) 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). 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: 90121). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 16451135, 28449805). This variant is not present in population databases (gnomAD no frequency).
Myriad Genetics, Inc.	RCV003451122	SCV004186416	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-12	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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529525	SCV001743115	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001529525	SCV001959950	pathogenic	not provided		no assertion criteria provided	clinical testing