ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2560G>A (p.Ala854Thr) (rs574371474)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000217218 SCV000274054 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-29 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000222472 SCV000279153 uncertain significance not provided 2017-08-14 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2560G>A at the cDNA level, p.Ala854Thr (A854T) at the protein level, and results in the change of an Alanine to a Threonine (GCC>ACC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Ala854Thr was not observed in large population cohorts (Lek 2016). Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Ala854Thr occurs at a position that is conserved through mammals and is located in the endonuclease 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 Ala854Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000530024 SCV000625627 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-02 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 854 of the PMS2 protein (p.Ala854Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. The frequency data for this variant in the population databases (ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 230486). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 RCV000764718 SCV000895853 uncertain significance Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 4 2018-10-31 criteria provided, single submitter clinical testing
Constitutional Genetics Lab,Leon Berard Cancer Center RCV001249991 SCV001424005 uncertain significance Lynch-like syndrome 2019-07-01 no assertion criteria provided clinical testing

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