Submissions for variant NM_000249.4(MLH1):c.589C>T (p.Gln197Ter)

dbSNP: rs1553644123

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000563448	SCV000662053	pathogenic	Hereditary cancer-predisposing syndrome	2019-01-08	criteria provided, single submitter	clinical testing	The p.Q197* pathogenic mutation (also known as c.589C>T), located in coding exon 8 of the MLH1 gene, results from a C to T substitution at nucleotide position 589. This changes the amino acid from a glutamine to a stop codon within coding exon 8. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000629784	SCV000750740	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-05-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln197*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 479670). This variant has not been reported in the literature in individuals affected with MLH1-related conditions.
GeneDx	RCV000657721	SCV000779471	pathogenic	not provided	2024-05-08	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 at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 30787465)
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659868	SCV000781751	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2016-11-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000659868	SCV004186524	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.
Baylor Genetics	RCV000659868	SCV004193070	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2021-07-23	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000657721	SCV001549950	pathogenic	not provided		no assertion criteria provided	clinical testing	The MLH1 p.Gln197* variant was not identified in the literature nor was it identified in the dbSNP, or UMD-LSDB, databases. The variant was identified in ClinVar (classified as pathogenic by Invitae, Ambry Geneitics, GeneDx and one clinical laboratory). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Gln197* variant leads to a premature stop codon at position 197, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MLH1 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.