ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1775G>A (p.Ser592Asn) (rs587782621)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204209 SCV000260157 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2017-12-14 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 592 of the MLH1 protein (p.Ser592Asn). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 219961). 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, this variant has uncertain impact on MLH1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000213242 SCV000279749 uncertain significance not provided 2015-12-28 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1775G>A at the cDNA level, p.Ser592Asn (S592N) at the protein level, and results in the change of a Serine to an Asparagine (AGT>AAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Ser592Asn 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 Asparagine share similar properties, this is considered a conservative amino acid substitution. MLH1 Ser592Asn occurs at a position that is not conserved and is located in the region of interaction with PMS2/MLH3/PMS1 and the region of interaction with EXO1 (Raevaara 2005, UniProt). 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 Ser592Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000581549 SCV000689840 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-30 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764495 SCV000895566 uncertain significance Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2018-10-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000581549 SCV001173644 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-19 criteria provided, single submitter clinical testing Insufficient evidence

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