Submissions for variant NM_000249.4(MLH1):c.583A>T (p.Lys195Ter)

dbSNP: rs863225383

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216838	SCV000278462	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-06	criteria provided, single submitter	clinical testing	The p.K195* pathogenic mutation (also known as c.583A>T), located in coding exon 7 of the MLH1 gene, results from an A to T substitution at nucleotide position 583. This changes the amino acid from a lysine to a stop codon within coding exon 7. This mutation has been reported in a female diagnosed with MSI-H cancer of the cecum at age 44 that was MLH1 deficient (Hinrichsen I et al. Carcinogenesis 2015 Feb; 36(2):202-11) and in a 42 year-old with a rectal adenoma (Binder H et al. J. Pathol., 2017 Oct;243:242-254). 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	RCV000202144	SCV000779388	pathogenic	not provided	2017-10-31	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.583A>T at the cDNA level and p.Lys195Ter (K195X) at the protein level. The substitution creates a nonsense variant, which changes a Lysine to a premature stop codon (AAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in association with Lynch syndrome (Hinrichsen 2015, Binder 2017) and is considered pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000216838	SCV000908609	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 7 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 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.
Invitae	RCV002517340	SCV003525416	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-03-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects MLH1 function (PMID: 25477341). ClinVar contains an entry for this variant (Variation ID: 218025). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 25477341). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys195*) 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).
Myriad Genetics, Inc.	RCV003454512	SCV004187436	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017484	SCV004848301	likely pathogenic	Lynch syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Lys195X variant in MLH1 has been reported in 1 individual with colorectal cancer (Hinrichsen 2015). It was absent from large population studies and has been reported in ClinVar (Variation ID 218025). This nonsense variant leads to a premature termination codon at position 195, which is predicted to lead to a truncated or absent protein. Loss of function of the MLH1 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2
Mayo Clinic Laboratories, Mayo Clinic	RCV000202144	SCV000257105	likely pathogenic	not provided		no assertion criteria provided	research