ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.955G>A (p.Glu319Lys) (rs63750796)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115489 SCV000185511 likely benign Hereditary cancer-predisposing syndrome 2018-02-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Does not segregate with disease in family study (genes with incomplete penetrance),Other data supporting benign classification
Color RCV000115489 SCV000684885 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-22 criteria provided, single submitter clinical testing
Counsyl RCV000410221 SCV000489392 uncertain significance Lynch syndrome II 2016-09-29 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764484 SCV000895555 uncertain significance Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000656859 SCV000149398 uncertain significance not provided 2018-08-01 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.955G>A at the cDNA level, p.Glu319Lys (E319K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). This variant has been observed in at least two families with suspected Lynch Syndrome and three individuals with a personal history of breast cancer (Nilbert 2009, Tung 2015, Lagerstedt-Robinson 2016, Shirts 2016, Rummel 2017). An alternate missense variant, c.954_955delCGinsTA, which leads to the same amino acid change observed in this case, Glu319Lys, was observed in a Turkish case of early-onset colorectal cancer that exhibited microsatellite instability and loss of MLH1 protein expression by immunohistochemistry, in a pedigree meeting Amsterdam II Lynch syndrome criteria (Tunca 2010). MLH1 Glu319Lys was observed at an allele frequency of 0.01% (15/126,622) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the N-terminal ATPase domain (Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MLH1 Glu319Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GenomeConnect, ClinGen RCV000656859 SCV000986701 not provided not provided no assertion provided phenotyping only Variant interpretted as Uncertain significance and reported on 11/29/2017 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Invitae RCV000524325 SCV000260533 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 319 of the MLH1 protein (p.Glu319Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs63750796, ExAC 0.01%). This variant has been reported in individuals affected with breast cancer (PMID: 26845104, 25186627), and either early-onset colorectal cancer or suspected-Lynch syndrome (PMID: 18566915, 27601186). A different variant (c.954_955delinsTA) giving rise to the same protein effect observed here (p.Glu319Lys) has been reported in an individual affected with early-onset colon cancer, whose family met Amsterdam II Lynch syndrome criteria (PMID: 20373145). ClinVar contains an entry for this variant (Variation ID: 90452). 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 disruptive, 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.
Pathway Genomics RCV000144597 SCV000189924 uncertain significance Lynch syndrome I 2014-07-24 no assertion criteria provided clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212528 SCV000601418 uncertain significance not specified 2017-05-10 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000075945 SCV000266184 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing

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