ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1637A>G (p.Lys546Arg) (rs587779954)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000759809 SCV000149372 uncertain significance not provided 2016-07-13 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1637A>G at the cDNA level, p.Lys546Arg (K546R) at the protein level, and results in the change of a Lysine to an Arginine (AAG>AGG). This variant was observed in cohort of 1250 individuals with personal history of Lynch syndrome-associated cancer and/or polyps undergoing multi-gene panel testing (Yurgelun 2015). MLH1 Lys546Arg 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 Lysine and Arginine share similar properties, this is considered a conservative amino acid substitution. MLH1 Lys546Arg occurs at a position where amino acids with properties similar to Lysine are tolerated across species and is located in region of interaction with EXO1, PMS1, PMS2, and MLH3 (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 Lys546Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
CSER _CC_NCGL, University of Washington RCV000211532 SCV000212178 uncertain significance Lynch syndrome 2015-03-11 criteria provided, single submitter research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000115463 SCV000592412 uncertain significance not specified 2014-12-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV000566461 SCV000662039 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-20 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000625759 SCV000746301 likely pathogenic Hereditary breast and ovarian cancer syndrome 2017-12-03 criteria provided, single submitter clinical testing
Invitae RCV000629933 SCV000750889 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-30 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 546 of the MLH1 protein (p.Lys546Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs587779954, ExAC 0.001%). This variant has been reported in an individual with suspected Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 127617). 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.
Counsyl RCV000662406 SCV000784829 uncertain significance Lynch syndrome II 2016-12-27 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759809 SCV000889386 uncertain significance not provided 2018-05-08 criteria provided, single submitter clinical testing
Color RCV000566461 SCV000908638 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-12 criteria provided, single submitter clinical testing

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