ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.755C>G (p.Ser252Ter)

dbSNP: rs63750198
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001026562 SCV001188968 pathogenic Hereditary cancer-predisposing syndrome 2018-09-04 criteria provided, single submitter clinical testing The p.S252* pathogenic mutation (also known as c.755C>G), located in coding exon 9 of the MLH1 gene, results from a C to G substitution at nucleotide position 755. This changes the amino acid from a serine to a stop codon within coding exon 9. 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). 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.
Myriad Genetics, Inc. RCV003455137 SCV004189734 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.
Invitae RCV003594086 SCV004293455 pathogenic Hereditary nonpolyposis colorectal neoplasms 2023-05-02 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 827123). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 25980754). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser252*) 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).

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