Submissions for variant NM_000249.4(MLH1):c.1276C>T (p.Gln426Ter)

dbSNP: rs63750316

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075164	SCV000106155	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000571335	SCV000676029	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-24	criteria provided, single submitter	clinical testing	The p.Q426* pathogenic mutation (also known as c.1276C>T), located in coding exon 12 of the MLH1 gene, results from a C to T substitution at nucleotide position 1276. This changes the amino acid from a glutamine to a stop codon within coding exon 12. This mutation has been detected in multiple families with Lynch syndrome (Jäger AC et al. Oncogene. 2001 Jun;20:3590-5; Bisgaard ML et al. Hum. Mutat. 2002 Jul;20:20-7; Valentin MD et al. Fam. Cancer. 2011 Dec;10:641-7; Frostberg E. et al. Cancers (Basel). 2021 Oct;13(20)) including a patient with medulloblastoma at age 5 (Therkildsen C et al. Eur. J. Neurol. 2015 Apr;22:717-24). This mutation has specifically been reported in multiple Brazilian families with Lynch syndrome (Schneider NB et al. Cancer Med 2018 May;7:2078-2088; Rossi BM et al. BMC Cancer 2017 Sep;17:623). Of note, this alteration is designated as Q426X, Gln426X, p.Gln426Ter, and p.Gln426* in published 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.
Color Diagnostics, LLC DBA Color Health	RCV000571335	SCV000689799	pathogenic	Hereditary cancer-predisposing syndrome	2017-07-05	criteria provided, single submitter	clinical testing
Invitae	RCV000690382	SCV000818066	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-03-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 89691). This premature translational stop signal has been observed in individual(s) with clinical features of MLH1-related conditions (PMID: 12112654, 24090359, 24344984, 25648859, 26437257, 28874130, 28944238). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln426*) 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).
Mendelics	RCV000075164	SCV000838012	pathogenic	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000075164	SCV000914320	pathogenic	Lynch syndrome	2019-01-30	criteria provided, single submitter	research
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV003129769	SCV003808055	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2022-06-10	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 strong, PM2 moderated
Myriad Genetics, Inc.	RCV003129769	SCV004186408	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 termination codon and is predicted to result in premature protein truncation.