ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.794G>C (p.Arg265Pro) (rs63751448)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000680199 SCV000807663 likely pathogenic Lynch syndrome I 2018-06-13 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability > 0.95 (0.969)
Ambry Genetics RCV000567811 SCV000673828 likely pathogenic Hereditary cancer-predisposing syndrome 2019-10-10 criteria provided, single submitter clinical testing The p.R265P variant (also known as c.794G>C), located in coding exon 10 of the MLH1 gene, results from a G to C substitution at nucleotide position 794. The arginine at codon 265 is replaced by proline, an amino acid with dissimilar properties. This variant was detected in an individual with microsatellite high (MSI-H) colorectal cancer at age 57 who was also diagnosed with synchronous pancreatic cancer and MSI-H sebaceous carcinoma. All three tumors showed absence of the MLH1 protein (Tanyi et al. Eur J Surg Oncol. 2009 Oct; 35 (10): 1128-30; Tanyi et al. Eur J Surg Oncol. 2014 Nov; 40(11):1445-52). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in function (Tempel, W, et al. Crystal Structure of human MLH1. Structural Genomics Consortium. Protein Data Bank, accessed 10/13/2015. DOI:10.2210/pdb4P7A/pdb). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV001212266 SCV001383846 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-03-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 265 of the MLH1 protein (p.Arg265Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with clinical features of Lynch syndrome (PMID: 28874130, 24344984), and observed to segregate with Lynch syndrome in a family (PMID: 19423266). ClinVar contains an entry for this variant (Variation ID: 433856). Based on a multifactorial likelihood algorithm using genetic data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). This variant has been reported to affect MLH1 protein function (PMID: 29520894). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355963 SCV001550999 uncertain significance not provided no assertion criteria provided clinical testing

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