Submissions for variant NM_000249.4(MLH1):c.1381A>T (p.Lys461Ter)

dbSNP: rs63750540

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000030213	SCV000106177	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030213	SCV000052880	pathogenic	Lynch syndrome	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Pathogenic.
Ambry Genetics	RCV000132422	SCV000187515	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-13	criteria provided, single submitter	clinical testing	The p.K461* pathogenic mutation (also known as c.1381A>T), located in coding exon 12 of the MLH1 gene, results from an A to T substitution at nucleotide position 1381. This changes the amino acid from a lysine to a stop codon within coding exon 12. This mutation has been reported in multiple hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome families, and has been shown to disrupt normal mRNA processing (Kitaeva MN et al. Cancer Res., 1997 Oct;57:4478-81; Syngal S et al. JAMA, 1999 Jul;282:247-53; Terdiman JP et al. Gastroenterology, 2001 Jan;120:21-30; Stella A et al. Cancer Res., 2001 Oct;61:7020-4; Wagner A et al. Am J Hum Genet, 2003 May;72:1088-100; Mueller J et al. Cancer Res, 2009 Sep;69:7053-61; Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Cloyd JM et al. J Gastrointest Cancer, 2018 Mar;49:93-96). 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.
GeneDx	RCV000202201	SCV000279082	pathogenic	not provided	2022-05-26	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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Syngal 1999, Stella 2001, Terdiman 2001, Mueller 2009); Published functional studies demonstrate a partial splicing defect, with skipping of exon 12 in some transcripts (Stella 2001, Lastella 2004); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15173238, 12658575, 25345868, 19690142, 11585727, 25525159, 11208710, 22658618, 21155023, 30322717, 9377556, 10422993, 19931546, 27978560, 29238914, 30019097, 28944238, 28449805, 32040686, 31447099)
Invitae	RCV000524235	SCV000284017	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys461*) in the MLH1 gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and may result in an absent or disrupted protein product. 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: 9377556, 10422993, 11208710, 11585727, 12658575, 19690142). ClinVar contains an entry for this variant (Variation ID: 36540). Studies have shown that this premature translational stop signal results in skipping of exon 12 and introduces a premature termination codon (PMID: 11585727, 15173238; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202201	SCV000601354	pathogenic	not provided	2021-08-27	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. The variant was found in at least one symptomatic patient, and not found in general population data. In the literature, the variant has been reported in multiple LS and CRC pts that were MMR deficient. Experiments have shown that this variant results in partial splicing defect resulting in exon 12 skipping in some of the transcripts which was reported in LS families.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000030213	SCV000711429	pathogenic	Lynch syndrome	2016-12-08	criteria provided, single submitter	clinical testing	The p.Lys461X variant in MLH1 has been reported in at least 5 individuals with L ynch Syndrome (Kitaeva 1997, Sygnal 1999, Stella 2001, Wagner 2003, Mueller 2009 ) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 461 which is predicted to lead to a tru ncated or absent protein. Furthermore, this variant has been classified as Patho genic on Sept. 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV 000106177.2). In summary, this variant meets criteria to be classified as pathog enic for Lynch Syndrome in an autosomal dominant manner based upon the predicted impact to the protein.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659871	SCV000781756	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2016-11-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763102	SCV000893644	pathogenic	Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2	2018-10-31	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000659871	SCV001190319	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2019-08-21	criteria provided, single submitter	research
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000659871	SCV003928053	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-20	criteria provided, single submitter	clinical testing	The MLH1 c.1381A>T (p.Lys461Ter) change is a nonsense variant that is predicted to cause premature protein truncation or absence of protein due to nonsense-mediated decay. This variant has also been shown to cause exon 12 skipping in some transcripts (PMID: 11585727, 15173238). This alteration has been reported in several individuals with Lynch syndrome (PMID: 29238914, 19690142, 10422993, 30877237, 12658575, 11208710). It has also been identified in an individual diagnosed with glioblastoma whose tumor has a ultra-hypermutator phenotype (internal data). This variant is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic.
Myriad Genetics, Inc.	RCV000659871	SCV004190033	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-20	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. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 11585727].
Baylor Genetics	RCV000659871	SCV004193003	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-05-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132422	SCV004359229	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-18	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 12 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 individuals affected with Lynch syndrome and Lynch syndrome-associated cancer (PMID: 19690142, 27978560, 28449805, 29238914, 30322717). RNA studies have shown this variant results in partial exon skipping of exon 12 (PMID: 11585727, 15173238). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202201	SCV000257051	pathogenic	not provided		no assertion criteria provided	research
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001249929	SCV001423871	pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing
GeneReviews	RCV001804748	SCV002054060	not provided	Lynch syndrome 1		no assertion provided	literature only