Submissions for variant NM_000249.4(MLH1):c.578C>G (p.Ser193Ter)

dbSNP: rs63751480

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075767	SCV000106775	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Invitae	RCV001854305	SCV002191737	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2021-07-04	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: 90278). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 15849733). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser193*) 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).
Ambry Genetics	RCV002354263	SCV002653046	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-09	criteria provided, single submitter	clinical testing	The p.S193* pathogenic mutation (also known as c.578C>G), located in coding exon 7 of the MLH1 gene, results from a C to G substitution at nucleotide position 578. This changes the amino acid from a serine to a stop codon within coding exon 7. This mutation was reported in one of 1721 unrelated, mostly German individuals with suspected hereditary nonpolyposis colorectal cancer (HNPCC) (Mangold E et al. Int. J. Cancer 2005 Sep;116:692-702). This alteration was also identified in an individual with three metachronous colon cancers diagnosed at ages 26, 37, and 39 years old whose cecal tumor demonstrated microsatellite instability and loss of MLH1 and PMS2 protein expression by immunohistochemistry (Overbeek LI et al. Br. J. Cancer 2007 May;96:1605-12). 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003321498	SCV004026098	pathogenic	not provided	2022-08-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003452750	SCV004188748	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-17	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.