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

dbSNP: rs63750540

Total submissions: 18

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; Ambry internal data). 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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524235	SCV000284017	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-11-11	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 altered 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). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MLH1 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MLH1 testing. 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 produces a non-functional protein and/or introduces a premature termination codon (PMID: 11585727, 15173238; internal data). 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	2024-03-25	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000202201	SCV005878984	pathogenic	not provided	2024-04-19	criteria provided, single submitter	clinical testing	The MLH1 c.1381A>T; p.Lys461Ter variant (rs63750540; ClinVar ID: 36540) is reported in the literature in multiple individuals and families affected with Lynch syndrome (Mueller 2009, Stella 2001, Sunga 2017, Syngal 1999, Terdiman 2001). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, RNA analyses suggest that in some transcripts this variant leads to skipping of exon 12, which is predicted to result in a frameshift (Lastella 2004, Stella 2001). Based on available information, this variant is considered to be pathogenic. References: Lastella P et al. Site directed mutagenesis of hMLH1 exonic splicing enhancers does not correlate with splicing disruption. J Med Genet. 2004 Jun;41(6):e72. PMID: 15173238. Mueller J et al. Comprehensive molecular analysis of mismatch repair gene defects in suspected Lynch syndrome (hereditary nonpolyposis colorectal cancer) cases. Cancer Res. 2009 Sep 1;69(17):7053-61. PMID: 19690142. Stella A et al. A nonsense mutation in MLH1 causes exon skipping in three unrelated HNPCC families. Cancer Res. 2001 Oct 1;61(19):7020-4. PMID: 11585727. Sunga AY et al. Spectrum of mismatch repair gene mutations and clinical presentation of Hispanic individuals with Lynch syndrome. Cancer Genet. 2017 Apr;212-213:1-7. PMID: 28449805. Syngal S et al. Interpretation of genetic test results for hereditary nonpolyposis colorectal cancer: implications for clinical predisposition testing. JAMA. 1999 Jul 21;282(3):247-53. PMID: 10422993. Terdiman JP et al. Efficient detection of hereditary nonpolyposis colorectal cancer gene carriers by screening for tumor microsatellite instability before germline genetic testing. Gastroenterology. 2001 Jan;120(1):21-30. PMID: 11208710.
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