ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3762A>T (p.Glu1254Asp) (rs375459388)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000524187 SCV000166234 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-01-07 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 1254 of the MSH6 protein (p.Glu1254Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is present in population databases (rs375459388, ExAC 0.07%). This variant has been observed in an individual with colorectal cancer (PMID: 30521064). ClinVar contains an entry for this variant (Variation ID: 89457). 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.
GeneDx RCV000212689 SCV000211327 uncertain significance not specified 2017-07-03 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3762A>T at the cDNA level, p.Glu1254Asp (E1254D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAA>GAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Glu1254Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamic Acid and Aspartic Acid share similar properties, this is considered a conservative amino acid substitution. MSH6 Glu1254Asp occurs at a position that is not conserved and is located in domain V of the MutS domain (Terui 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Glu1254Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000160699 SCV000215311 likely benign Hereditary cancer-predisposing syndrome 2018-09-12 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Counsyl RCV000408995 SCV000487880 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2015-11-24 criteria provided, single submitter clinical testing
Color RCV000160699 SCV000685443 likely benign Hereditary cancer-predisposing syndrome 2020-02-10 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587284 SCV000695887 uncertain significance not provided 2016-02-01 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3762A>T variant affects a conserved nucleotide, resulting in amino acid change from Glu to Asp. 4/5 in-silico tools predict this variant to be benign. This variant is found in 6/121264 control chromosomes at a frequency of 0.0000495, with the highest allele frequency in East Asians (6/8650). The East Asian allele frequency is nearly 5-fold greater than the maximal expected frequency of a pathogenic MASH6 allele (0.0001421), suggesting that this variant may be a benign polymorphism found in East Asians. Several diagnostic clinical laboratories classified this variant as a VUS; however, this classification was made before the ExAC database, when few Asian control chromosomes were available for variant interpretation. 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. Additionally, at least one lab predicted the variant to be neutral based on in bioinformatics (PONMMR; Ali et al 2012)). Taken together, because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS)-possibly benign until additional information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587284 SCV001134441 uncertain significance not provided 2018-10-02 criteria provided, single submitter clinical testing

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