Submissions for variant NM_000179.2(MSH6):c.1652G>A (p.Gly551Asp) (rs587779917)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115380	SCV000149289	uncertain significance	not provided	2015-10-27	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.1652G>A at the cDNA level, p.Gly551Asp (G551D) at the protein level, and results in the change of a Glycine to an Aspartic Acid (GGC>GAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Gly551Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glycine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Gly551Asp occurs at a position that is conserved across species and is located in domain II 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 information, it is unclear whether MSH6 Gly551Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000216184	SCV000275797	uncertain significance	Hereditary cancer-predisposing syndrome	2015-05-14	criteria provided, single submitter	clinical testing	Insufficient evidence
Invitae	RCV000473749	SCV000551293	uncertain significance	Hereditary nonpolyposis colon cancer	2019-07-10	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with aspartic acid at codon 551 of the MSH6 protein (p.Gly551Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 127562). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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.
Counsyl	RCV000662991	SCV000785982	uncertain significance	Hereditary nonpolyposis colorectal cancer type 5	2018-01-29	criteria provided, single submitter	clinical testing

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