ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1092T>A (p.Asp364Glu) (rs370066853)

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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 RCV000217971 SCV000275268 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-07 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (benign)
Invitae RCV000475489 SCV000551943 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-31 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 364 of the PMS2 protein (p.Asp364Glu). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is present in population databases (rs370066853, ExAC 0.001%). This variant has been reported in an individual affected with breast cancer (PMID: 26976419). ClinVar contains an entry for this variant (Variation ID: 231423). 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 glutamic 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.
GeneDx RCV000484259 SCV000565394 uncertain significance not provided 2017-08-04 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1092T>A at the cDNA level, p.Asp364Glu (D364E) at the protein level, and results in the change of an Aspartic Acid to a Glutamic Acid (GAT>GAA). This variant was observed in 1/488 women with breast cancer undergoing testing for a 25 cancer susceptibility gene panel (Tung 2016). PMS2 Asp364Glu was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Aspartic Acid and Glutamic Acid share similar properties, this is considered a conservative amino acid substitution. PMS2 Asp364Glu occurs at a position that is not conserved across species and is located within the ATPase domain (Guarne 2001, Fukui 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure or function. Based on currently available evidence, it is unclear whether PMS2 Asp364Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000217971 SCV000903600 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-19 criteria provided, single submitter clinical testing

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