ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2173A>G (p.Ile725Val) (rs148898662)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212660 SCV000149297 uncertain significance not provided 2018-04-27 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2173A>G at the cDNA level, p.Ile725Val (I725V) at the protein level, and results in the change of an Isoleucine to a Valine (ATC>GTC). This variant has been observed in at least one individual with breast cancer (Tung 2015). MSH6 Ile725Val was observed at an allele frequency of 0.05% (14/30,782) in individuals of South Asian ancestry in large population cohorts (Lek 2016). MSH6 Ile725Val is located within the Lever 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 Ile725Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115388 SCV000184558 likely benign Hereditary cancer-predisposing syndrome 2018-05-22 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Invitae RCV000204867 SCV000261448 uncertain significance Hereditary nonpolyposis colon cancer 2019-11-23 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 725 of the MSH6 protein (p.Ile725Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs148898662, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in an individual affected with breast cancer (PMID: 11709755). ClinVar contains an entry for this variant (Variation ID: 127569). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be tolerated (PMID: 22290698). However, this prediction has not been confirmed by published functional studies and its 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.
Color RCV000115388 SCV000910784 likely benign Hereditary cancer-predisposing syndrome 2015-01-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781575 SCV000919730 uncertain significance not specified 2017-11-24 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.2173A>G (p.Ile725Val) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a benign outcome for this variant . This variant was found in 28/276672 control chromosomes, predominantly observed in the South Asian subpopulation at a frequency of 0.000455 (14/30782). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421), suggesting this is likely a benign polymorphism found primarily in the populations of South Asian origin. The variant has been reported in a breast cancer and ALL patient (BCR-ABL translocation positive) in the literature, without strong evidence for causality (Tung_2014, Zhang_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS - possibly normal variant.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212660 SCV001134406 uncertain significance not provided 2019-05-10 criteria provided, single submitter clinical testing
Mendelics RCV000986720 SCV001135816 likely benign Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing

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