ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2048T>C (p.Phe683Ser) (rs587778972)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075497 SCV000106493 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Posterior probability=0.990 therefore Class 4 because not greater than 0.99
GeneDx RCV000589365 SCV000279952 uncertain significance not provided 2017-10-17 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.2048T>C at the cDNA level, p.Phe683Ser (F683S) at the protein level, and results in the change of a Phenylalanine to a Serine (TTC>TCC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Phe683Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Phenylalanine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Phe683Ser occurs at a position that is conserved across species and is located within the region of interaction with PMS2/MLH3/PMS1 (Pang 1997, Raevaara 2005, Hardt 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Phe683Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000790627 SCV000696140 uncertain significance not specified 2019-04-24 criteria provided, single submitter clinical testing Variant summary: MLH1 c.2048T>C (p.Phe683Ser) results in a non-conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal domain (IPR032189) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251222 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. In the Leiden Open Variation database (LOVD), the variant has been reported in two individuals with colorectal cancer. To our knowledge, no occurrence of c.2048T>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported in the published peer-reviewed literature. Two other submitters including one expert panel have provided clinical significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. While the expert panel classifies the variant as likely pathogenic based on a posterior probability model another submitter reports a classification of uncertain significance. Therefore this variant is classified as uncertain significance until additional evidence becomes available.
Ambry Genetics RCV001014231 SCV001174916 likely pathogenic Hereditary cancer-predisposing syndrome 2019-04-24 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Moderate segregation with disease (at least 3 informative meioses) for rare diseases.;Rarity in general population databases (dbsnp, esp, 1000 genomes);Structural Evidence
Invitae RCV001209526 SCV001380964 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-18 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with serine at codon 683 of the MLH1 protein (p.Phe683Ser). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with Lynch syndrome associated cancers in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 90012). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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