ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1867C>G (p.Pro623Ala) (rs3136334)

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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 RCV000128867 SCV000172724 likely benign Hereditary cancer-predisposing syndrome 2017-07-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other data supporting benign classification
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034494 SCV000043357 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Color RCV000128867 SCV000902977 likely benign Hereditary cancer-predisposing syndrome 2016-01-07 criteria provided, single submitter clinical testing
Counsyl RCV000662448 SCV000784919 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-02-15 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000074692 SCV000296879 uncertain significance Lynch syndrome 2015-10-30 criteria provided, single submitter clinical testing
GeneDx RCV000034494 SCV000279098 uncertain significance not provided 2018-02-15 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1867C>G at the cDNA level, p.Pro623Ala (P623A) at the protein level, and results in the change of a Proline to an Alanine (CCC>GCC). This variant was observed in an individual with atherosclerosis, with no specific information about cancer history (Johnston 2012). In an in vivo functional study, this variant was not resistant to a DNA damaging agent suggesting that it is not pathogenic (Houlleberghs 2017). MSH6 Pro623Ala was observed at an allele frequency of 0.13% (32/23,910) in individuals of African ancestry in large population cohorts (Lek 2016). MSH6 Pro623Ala is located in the Connector domain (Warren 2007, Kansikas 2011). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Pro623Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
ITMI RCV000121577 SCV000085773 not provided not specified 2013-09-19 no assertion provided reference population
Integrated Genetics/Laboratory Corporation of America RCV000034494 SCV000695798 uncertain significance not provided 2017-03-30 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.1867C>G (p.Pro623Ala) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant. This variant was found in 10/120356 control chromosomes in ExAC at a frequency of 0.0000831, and 34/276648 controls chromosomes in genoMAD (32/23910 Africans ie 0.001338, which exceeds the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421), suggesting this variant is likely a benign polymorphism primarily in Africans. In addition, multiple clinical diagnostic laboratories classified this variant as uncertain significance, and one other lab classified it as likely benign, all without evidence for independent evaluation. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Multiple publications developed prediction tools and classified variant as neutral/VUS (Ali_HM_2012, Terui_J Biomedical Science_2013, and Thompson_HM_2013b). Taken together, this variant is classified as VUS-possibly benign until more evidence becomes available.
Invitae RCV000524123 SCV000218546 likely benign Hereditary nonpolyposis colon cancer 2017-12-25 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000121577 SCV000601519 uncertain significance not specified 2016-12-09 criteria provided, single submitter clinical testing

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