ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3972G>C (p.Glu1324Asp) (rs587779938)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115426 SCV000149335 uncertain significance not provided 2013-10-08 criteria provided, single submitter clinical testing This variant is denoted c.3972G>C at the cDNA level, p.Glu1324Asp (E1324D) at the protein level, and results in the change of a Glutamic Acid codon to an Aspartic Acid codon (GAG>GAC) in exon 9. This variant is a conservative substitution of one uncharged, polar amino acid for another and alters a position that is well conserved throughout evolution. This variant is located within the MutS domain V and multiple in silico algorithms predict that this variant may be damaging to protein structure and function. E1324D has not been published in the literature as a mutation or as a benign polymorphism to our knowledge. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI ESP Exome Variant Server, suggesting it is not a common benign variant in these populations. Therefore, based on the currently available information, we consider this to be a variant of unknown significance. The variant is found in BR-OV-HEREDIC panel(s).
Counsyl RCV000409288 SCV000487920 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2015-12-01 criteria provided, single submitter clinical testing
Invitae RCV000704125 SCV000833060 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-09-24 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 1324 of the MSH6 protein (p.Glu1324Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid 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: 127595). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their 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.

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