ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.277A>G (p.Ser93Gly) (rs41295282)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212516 SCV000149386 likely benign not specified 2017-10-25 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000115477 SCV000217328 likely benign Hereditary cancer-predisposing syndrome 2019-03-05 criteria provided, single submitter clinical testing Intact protein function observed in appropriate functional assay(s);Other data supporting benign classification;Structural Evidence
Invitae RCV001085936 SCV000252648 benign Hereditary nonpolyposis colon cancer 2019-12-31 criteria provided, single submitter clinical testing
Counsyl RCV000409754 SCV000487952 uncertain significance Lynch syndrome II 2015-12-08 criteria provided, single submitter clinical testing
Color RCV000115477 SCV000910785 likely benign Hereditary cancer-predisposing syndrome 2015-01-19 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000524285 SCV001153833 uncertain significance not provided 2017-02-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212516 SCV001362944 likely benign not specified 2019-02-04 criteria provided, single submitter clinical testing Variant summary: MLH1 c.277A>G (p.Ser93Gly) results in a non-conservative amino acid change located in the DNA mismatch repair protein family, N-terminal and Histidine kinase/HSP90-like ATPase domains of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 277126 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.277A>G has been reported in the literature in affected individuals (Schneider_2018, Jansen_2016, Barnetson _2008, Hendriks _2003, Nystrom-Lahti_2002, Quaresima _1998). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Jansen_2016 reports a patient that carried the variant of interest along with another pathogenic germline MUTYH variant, c1187G>A (p.G396D) and a somatic MLH1 variant, c.281delT (p.(S95LfsX13), providing supporting evidence for a benign role. Several functional studies have been performed to assess the variant's impact on interaction and binding with PMS2 and Exo1, MMR activity, nuclear localization and expression, and splice pattern (Andersen_2012, Drost_2010, Takahashi_2007, Wanat_2007, Raevaara_2005, Nystrom-Lahti_2002, Ellison_2001). Thru these studies, the variant of interest was found to perform comparably to wild-type function. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign (1x), likely benign (2x) and once as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000212516 SCV000691843 likely benign not specified no assertion criteria provided clinical testing

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