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
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.
Ambry Genetics RCV000115489 SCV000185511 likely benign Hereditary cancer-predisposing syndrome 2019-03-06 criteria provided, single submitter clinical testing Does not segregate with disease in family study (genes with incomplete penetrance);Other data supporting benign classification
Invitae RCV000524325 SCV000260533 likely benign Hereditary nonpolyposis colon cancer 2019-12-22 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
Counsyl RCV000410221 SCV000489392 uncertain significance Lynch syndrome II 2016-09-29 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212528 SCV000601418 uncertain significance not specified 2017-05-10 criteria provided, single submitter clinical testing
Color RCV000115489 SCV000684885 uncertain significance Hereditary cancer-predisposing syndrome 2020-05-11 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
Pathway Genomics RCV000144597 SCV000189924 uncertain significance Lynch syndrome I 2014-07-24 no assertion criteria provided clinical testing
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.

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