Submissions for variant NM_000535.7(PMS2):c.675A>C (p.Glu225Asp) (rs876661233)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000217891	SCV000279856	uncertain significance	not provided	2016-02-03	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.675A>C at the cDNA level, p.Glu225Asp (E225D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAA>GAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Glu225Asp 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. PMS2 Glu225Asp occurs at a position where amino acids with properties similar to Glutamic Acid are tolerated across species and is located in the ATPase domain (Guarne 2001, Fukui 2011). 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 PMS2 Glu225Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000563797	SCV000664903	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-28	criteria provided, single submitter	clinical testing	Insufficient or conflicting evidence
Invitae	RCV000698159	SCV000826803	uncertain significance	Hereditary nonpolyposis colon cancer	2020-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid with aspartic acid at codon 225 of the PMS2 protein (p.Glu225Asp). The glutamic acid residue is moderately 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 PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 234813). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The aspartic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Fulgent Genetics,Fulgent Genetics	RCV000765964	SCV000897385	uncertain significance	Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 4	2018-10-31	criteria provided, single submitter	clinical testing

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