ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3354G>A (p.Glu1118=) (rs35642130)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001086511 SCV000261838 benign Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000429486 SCV000516862 benign not specified 2015-05-18 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 RCV000491525 SCV000580266 likely benign Hereditary cancer-predisposing syndrome 2015-05-01 criteria provided, single submitter clinical testing
Color RCV000491525 SCV000685393 benign Hereditary cancer-predisposing syndrome 2016-11-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000429486 SCV000919765 benign not specified 2018-04-23 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3354G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00043 in 246174 control chromosomes, predominantly at a frequency of 0.0034 within the South Asian subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 23.93 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.3354G>A in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000206593 SCV001134428 benign not provided 2019-07-12 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001137559 SCV001297511 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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