ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1857A>C (p.Glu619Asp) (rs63751121)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132230 SCV000187313 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-08 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000221704 SCV000279342 uncertain significance not provided 2016-02-18 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1857A>C at the cDNA level, p.Glu619Asp (E619D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAA>GAC). This variant has been reported in one individual with late-onset breast and endometrial cancer. The patient's endometrial tumor was reported to be microsatellite stable (MSS) and to have intact mismatch repair immunohistochemistry (MMR IHC) (Suchy 2006). MSH6 Glu619Asp was also observed to be present on the same allele (in cis) with a 4-bp deletion in MSH6 affecting a splice donor site in an individual with colorectal cancer at 34 and absence of MSH6 by IHC (Plaschke 2004). MSH6 Glu619Asp was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Glutamic Acid and Aspartic Acid share similar properties, this is considered a conservative amino acid substitution. MSH6 Glu619Asp occurs at a position where amino acids with properties similar to Glutamic Acid are tolerated 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 Glu619Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000524122 SCV000551282 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-27 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 619 of the MSH6 protein (p.Glu619Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is present in population databases (rs63751121, ExAC 0.006%). This variant has been reported in an individual with breast and endometrial cancer (PMID: 16813607) and in individuals with colorectal cancer (PMID: 15483016, 27601186). However, in one of the individuals with colorectal cancer, this variant was reported to occur on the same chromosome (in cis) with a pathogenic variant in MSH6 (PMID: 15483016). ClinVar contains an entry for this variant (Variation ID: 89228). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). However, an algorithm developed specifically for the MSH6 gene (PMID: 23621914), suggests that this missense change is likely to be tolerated. These predictions have not been confirmed by published functional studies. 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 RCV000132230 SCV000685234 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-17 criteria provided, single submitter clinical testing

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