ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1775G>C (p.Ser592Thr) (rs587782621)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132004 SCV000187063 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-31 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (benign)
Invitae RCV000524250 SCV000254359 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces serine with threonine at codon 592 of the MLH1 protein (p.Ser592Thr). The serine residue is moderately conserved and there is a small physicochemical difference between serine and threonine. This variant is present in population databases (rs587782621, ExAC 0.001%). This variant has been observed in individuals affected with pancreatic cancer, however one of them also carried a variant in the CDKN2A gene (PMID: 27449771, 29368341). ClinVar contains an entry for this variant (Variation ID: 142658). 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.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000199682 SCV000296891 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
GeneDx RCV000483590 SCV000565162 uncertain significance not provided 2018-03-08 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1775G>C at the cDNA level, p.Ser592Thr (S592T) at the protein level, and results in the change of a Serine to a Threonine (AGT>ACT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Ser592Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Serine and Threonine share similar properties, this is considered a conservative amino acid substitution. MLH1 Ser592Thr is located in the region of interaction with EXO1, PMS2, MLH3, and PMS1 (Raevaara 2005, Kansikas 2011, Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether MLH1 Ser592Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000132004 SCV000684771 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-11 criteria provided, single submitter clinical testing
Counsyl RCV000662692 SCV000785420 uncertain significance Lynch syndrome II 2017-08-01 criteria provided, single submitter clinical testing

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