Submissions for variant NM_000249.4(MLH1):c.955G>T (p.Glu319Ter)

dbSNP: rs63750796

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075946	SCV000106964	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Invitae	RCV001034666	SCV000253794	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2021-11-30	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: 90453). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 11748856, 15289847). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu319*) 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).
GeneDx	RCV000578913	SCV000680548	pathogenic	not provided	2017-03-01	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.955G>T at the cDNA level and p.Glu319Ter (E319X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MLH1 Glu319Ter has been observed in associated with colon and gastric cancer (Godino 2001). This variant is considered pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000656559	SCV000778602	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2018-02-27	criteria provided, single submitter	research
Ambry Genetics	RCV001019484	SCV001180848	pathogenic	Hereditary cancer-predisposing syndrome	2021-02-09	criteria provided, single submitter	clinical testing	The p.E319* pathogenic mutation (also known as c.955G>T), located in coding exon 11 of the MLH1 gene, results from a G to T substitution at nucleotide position 955. This changes the amino acid from a glutamic acid to a stop codon within coding exon 11. This alteration has been reported in a Spanish family who met Amsterdam criteria for Lynch syndrome (Godino J et al. Hum. Mutat., 2001 Dec;18:549). 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.	RCV000656559	SCV004186450	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-18	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.