ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.2070C>G (p.Tyr690Ter)

dbSNP: rs550890395
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000796222 SCV000935727 pathogenic Hereditary nonpolyposis colorectal neoplasms 2023-10-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr690*) in the MLH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 67 amino acid(s) of the MLH1 protein. This variant is not present in population databases (gnomAD no frequency). A different variant (c.2070C>A) giving rise to the same protein effect has been determined to be pathogenic (Invitae). This suggests that this variant is also likely to be causative of disease. ClinVar contains an entry for this variant (Variation ID: 642710). This variant disrupts a region of the MLH1 protein in which other variant(s) (p.Tyr750*, p.Lys732*, p.Ser726*) have been determined to be pathogenic (PMID: 10923051, 12799449, 16338176, 20533529; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001014284 SCV001174978 pathogenic Hereditary cancer-predisposing syndrome 2022-02-17 criteria provided, single submitter clinical testing The p.Y690* pathogenic mutation (also known as c.2070C>G), located in coding exon 18 of the MLH1 gene, results from a C to G substitution at nucleotide position 2070. This changes the amino acid from a tyrosine to a stop codon within coding exon 18. This alteration occurs at the 3' terminus of theMLH1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 67 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Clinical Genetics and Genomics, Karolinska University Hospital RCV001269507 SCV001449545 pathogenic not provided 2019-11-19 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002507374 SCV002809742 likely pathogenic Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2 2021-07-13 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV003453648 SCV004186518 pathogenic Colorectal cancer, hereditary nonpolyposis, type 2 2023-07-25 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.

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