ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1067C>T (p.Ser356Phe) (rs749334262)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000200267 SCV000254345 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 356 of the MLH1 protein (p.Ser356Phe). The serine residue is weakly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs749334262, ExAC 0.01%). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 216329). 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 tolerated, 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 RCV000220017 SCV000277009 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000482737 SCV000567887 uncertain significance not provided 2017-02-06 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1067C>T at the cDNA level, p.Ser356Phe (S356F) at the protein level, and results in the change of a Serine to a Phenylalanine (TCT>TTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Ser356Phe 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 Serine and Phenylalanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Ser356Phe occurs at a position that is not conserved and is not located in a functional domain (UniProt, Raevaara 2005). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Ser356Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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