ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.884G>C (p.Ser295Thr)

dbSNP: rs63750144
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075909 SCV000106926 uncertain significance Lynch syndrome 2018-06-13 reviewed by expert panel curation G>non-G at last base of exon with first 6 intronic bases not GTRRGT; Insufficient evidence
Labcorp Genetics (formerly Invitae), Labcorp RCV000630082 SCV000751038 pathogenic Hereditary nonpolyposis colorectal neoplasms 2022-05-27 criteria provided, single submitter clinical testing Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 26761715). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 90416). This variant has been observed in individual(s) with Lynch Syndrome (PMID: 9399661). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 295 of the MLH1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MLH1 protein. This variant also falls at the last nucleotide of exon 10, which is part of the consensus splice site for this exon. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.884G nucleotide in the MLH1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 12200596, 22949379, 26761715). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing.
Myriad Genetics, Inc. RCV003452785 SCV004185628 likely pathogenic Colorectal cancer, hereditary nonpolyposis, type 2 2023-07-18 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 15713769, 18561205, 16395668, 17653898].

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.