Submissions for variant NM_000249.4(MLH1):c.1534G>T (p.Glu512Ter)

dbSNP: rs63751472

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075236	SCV000106229	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
GeneDx	RCV001786332	SCV002028835	pathogenic	not provided	2021-11-24	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Scott 2001, Mangold 2005); This variant is associated with the following publications: (PMID: 25525159, 11112663, 16216036)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001854291	SCV002233917	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-07-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu512*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 11112663). ClinVar contains an entry for this variant (Variation ID: 89762). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002399430	SCV002706691	pathogenic	Hereditary cancer-predisposing syndrome	2018-11-08	criteria provided, single submitter	clinical testing	The p.E512* pathogenic mutation (also known as c.1534G>T), located in coding exon 13 of the MLH1 gene, results from a G to T substitution at nucleotide position 1534. This changes the amino acid from a glutamic acid to a stop codon within coding exon 13. This mutation has been reported in an individual from a cohort of 95 families that either met Amsterdam criteria or Bethesda guidelines (Scott R.J. et al. Am. J. Hum. Genet. 2001 Jan; 68(1):118-127). This alteration has also been detected in the colorectal tumor sample showing loss of MLH1 by IHC of an individual who was known to carry the mutation in their germline (Mangold E. et al. J. Pathol. 2005 Dec; 207(4):385-95). 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.	RCV003451031	SCV004187702	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-20	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.