ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1117G>A (p.Gly373Arg) (rs766904735)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166495 SCV000217294 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000166495 SCV000904056 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-30 criteria provided, single submitter clinical testing
Counsyl RCV000662540 SCV000785117 uncertain significance Lynch syndrome II 2017-04-21 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764487 SCV000895558 uncertain significance Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000484742 SCV000569576 uncertain significance not provided 2016-11-29 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1117G>A at the cDNA level, p.Gly373Arg (G373R) at the protein level, and results in the change of a Glycine to an Arginine (GGA>AGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Gly373Arg 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 Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Gly373Arg occurs at a position that is conserved in mammals and is not located in a known functional domain (Hardt 2011, 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 Gly373Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000226857 SCV000284005 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-26 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 373 of the MLH1 protein (p.Gly373Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs766904735, ExAC 0.02%). This variant has been observed in an individual affected with acute lymphoblastic leukemia  (PMID: 26580448). ClinVar contains an entry for this variant (Variation ID: 186843). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Mendelics RCV000708919 SCV000838009 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing

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