ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1261A>G (p.Ser421Gly) (rs755898663)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214831 SCV000276143 uncertain significance Hereditary cancer-predisposing syndrome 2015-06-08 criteria provided, single submitter clinical testing in silico models in agreement (benign);Insufficient or Conflicting Evidence
GeneDx RCV000219268 SCV000279931 uncertain significance not provided 2016-02-26 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1261A>G at the cDNA level, p.Ser421Gly (S421G) at the protein level, and results in the change of a Serine to a Glycine (AGT>GGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Ser421Gly 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 Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Ser421Gly occurs at a position that is not conserved and is located in the region of interaction with EXO1 (Uniprot). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether MLH1 Ser421Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000233979 SCV000284013 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-06-14 criteria provided, single submitter clinical testing This sequence change replaces serine with glycine at codon 421 of the MLH1 protein (p.Ser421Gly). The serine residue is weakly conserved and there is a small physicochemical difference between serine and glycine. This variant is present in population databases (rs755898663, ExAC 0.001%). This variant has been reported in an individual in the Universal Mutation Database (PMID: 23729658). ClinVar contains an entry for this variant (Variation ID: 232095). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glycine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Counsyl RCV000662471 SCV000784965 uncertain significance Lynch syndrome II 2017-02-22 criteria provided, single submitter clinical testing
Color RCV000214831 SCV001358436 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-22 criteria provided, single submitter clinical testing

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