ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2051A>C (p.Tyr684Ser) (rs267607886)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485347 SCV000566010 uncertain significance not provided 2015-03-24 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.2051A>C at the cDNA level, p.Tyr684Ser (Y684S) at the protein level, and results in the change of a Tyrosine to a Serine (TAT>TCT). MLH1 Tyr684Ser has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Tyr684Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Tyrosine and Serine differ in some properties, this is considered a semi-conservative amino acid substitution. MLH1 Tyr684Ser occurs at a position that is conserved across species and is located within the region of interaction with PMS2, MLH3,and PMS1 (Raevaara 2005). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MLH1 Tyr684Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000573920 SCV000669559 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-25 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000573920 SCV000689856 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-05 criteria provided, single submitter clinical testing
Invitae RCV001044170 SCV001207951 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-23 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with serine at codon 684 of the MLH1 protein (p.Tyr684Ser). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine 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 conditions. ClinVar contains an entry for this variant (Variation ID: 418728). 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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