Submissions for variant NM_000249.4(MLH1):c.1279C>T (p.Gln427Ter)

dbSNP: rs1559553501

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000692188	SCV000819999	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-10-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln427*) 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 Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 571138). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV002307594	SCV002601361	pathogenic	not provided	2022-05-10	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; Identified in an individual with Lynch syndrome in the published literature (Yurgelun 2015); This variant is associated with the following publications: (PMID: 25980754)
Ambry Genetics	RCV002386200	SCV002694621	pathogenic	Hereditary cancer-predisposing syndrome	2020-08-27	criteria provided, single submitter	clinical testing	The p.Q427* pathogenic mutation (also known as c.1279C>T), located in coding exon 12 of the MLH1 gene, results from a C to T substitution at nucleotide position 1279. This changes the amino acid from a glutamine to a stop codon within coding exon 12. This alteration was identified in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps. (Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20). This alteration has been previously identified in an individual from a North American cohort of individuals with early onset colon cancer. (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471). 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.	RCV003453448	SCV004186445	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 termination codon and is predicted to result in premature protein truncation.
All of Us Research Program, National Institutes of Health	RCV003999578	SCV004822622	pathogenic	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 12/19 of the MLH1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with mismatch repair deficient, early onset colorectal cancer (PMID: 27978560). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.