Submissions for variant NM_000535.7(PMS2):c.615G>T (p.Gln205His) (rs752499497)

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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	RCV000214892	SCV000275685	uncertain significance	Hereditary cancer-predisposing syndrome	2018-07-31	criteria provided, single submitter	clinical testing	Insufficient or conflicting evidence
Invitae	RCV000468010	SCV000552005	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2019-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine with histidine at codon 205 of the PMS2 protein (p.Gln205His). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and histidine. This variant is present in population databases (rs752499497, ExAC 0.006%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 231742). 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"). A different missense substitution at this codon (p.Gln205Pro) has been determined to be likely pathogenic (PMID: 18602922, 24027009). This suggests that the glutamine residue is critical for PMS2 protein function and that other missense substitutions at this position may also be pathogenic. 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	RCV000485595	SCV000565386	uncertain significance	not specified	2017-05-10	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.615G>T at the cDNA level, p.Gln205His (Q205H) at the protein level, and results in the change of a Glutamine to a Histidine (CAG>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Gln205His 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 Glutamine and Histidine differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 Gln205His occurs at a position that is conserved across species and is located in the ATPase domain (Fukui 2011). 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 PMS2 Gln205His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color	RCV000214892	SCV000686221	uncertain significance	Hereditary cancer-predisposing syndrome	2019-08-02	criteria provided, single submitter	clinical testing

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