ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.853C>T (p.Pro285Ser) (rs772374195)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482592 SCV000569710 uncertain significance not provided 2016-03-25 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.853C>T at the cDNA level, p.Pro285Ser (P285S) at the protein level, and results in the change of a Proline to a Serine (CCC>TCC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Pro285Ser 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 Proline and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Pro285Ser occurs at a position that is conserved across species and is located in the central region (Pang 1997). 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 Pro285Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000579470 SCV000684875 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-17 criteria provided, single submitter clinical testing
Invitae RCV000707382 SCV000836478 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-21 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 285 of the MLH1 protein (p.Pro285Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 420749). 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.
Ambry Genetics RCV000579470 SCV001179143 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-02 criteria provided, single submitter clinical testing Insufficient evidence

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