Submissions for variant NM_000249.4(MLH1):c.1050del (p.Gly351fs)

dbSNP: rs587778883

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075103	SCV000106093	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
GeneDx	RCV000115450	SCV000149359	pathogenic	not provided	2019-09-03	criteria provided, single submitter	clinical testing	Frameshift 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 individuals with a personal or family history consistent with pathogenic variants in this gene (Pastrello 2009, De Lellis 2013, Lagerstedt-Robinson 2016, Le 2017); This variant is associated with the following publications: (PMID: 26681312, 19449424, 19133695, 20052272, 28596308, 24278394, 27601186, 30585544)
Invitae	RCV001202542	SCV001373655	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2019-07-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). This variant has been observed in individuals with a personal and/or family history of Lynch syndrome-associated cancers (PMID: 19133695, 24278394, 26681312, 27601186). ClinVar contains an entry for this variant (Variation ID: 89633). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gly351Aspfs*16) in the MLH1 gene. It is expected to result in an absent or disrupted protein product.
Ambry Genetics	RCV002390214	SCV002703960	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-20	criteria provided, single submitter	clinical testing	The c.1050delA pathogenic mutation, located in coding exon 12 of the MLH1 gene, results from a deletion of one nucleotide at nucleotide position 1050, causing a translational frameshift with a predicted alternate stop codon (p.G351Dfs*16). This alteration has been detected in multiple unrelated individuals undergoing genetic testing based on a personal history of Lynch syndrome-associated cancer(s) (De Lellis L et al. PLoS One, 2013 Nov;8:e81194; Henriksson I et al. J Community Genet, 2019 Apr;10:259-266; Susswein LR et al. Genet Med, 2016 08;18:823-32). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.	RCV003455988	SCV004186422	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 frameshift predicted to result in premature protein truncation.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000115450	SCV001550828	uncertain significance	not provided		no assertion criteria provided	clinical testing