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 2021-03-25 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer, a Lynch syndrome-associated cancer, and/or polyps (Yurgelun 2015, Nikitin 2020); This variant is associated with the following publications: (PMID: 25980754, 32547938, 32719484)
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 2020-01-24 criteria provided, single submitter clinical testing The p.K546R variant (also known as c.1637A>G), located in coding exon 14 of the MLH1 gene, results from an A to G substitution at nucleotide position 1637. The lysine at codon 546 is replaced by arginine, an amino acid with highly similar properties. This alteration was identified in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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 2020-10-14 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 Health, Inc RCV000566461 SCV000908638 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-12 criteria provided, single submitter clinical testing

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