ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.506G>A (p.Arg169His) (rs730881917)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160898 SCV000211592 uncertain significance not provided 2017-10-27 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.506G>A at the cDNA level, p.Arg169His (R169H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Arg169His was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. PMS2 Arg169His occurs at a position that is conserved across species and is located in the ATPase domain (Guarne 2001). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Arg169His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance
Ambry Genetics RCV000215633 SCV000274795 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-22 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes) ;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Invitae RCV000465290 SCV000551973 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 169 of the PMS2 protein (p.Arg169His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with breast cancer (PMID: 30039884). ClinVar contains an entry for this variant (Variation ID: 182811). 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.
Color RCV000215633 SCV000691079 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-17 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000758687 SCV000887459 uncertain significance Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing PMS2 NM_000535.5:c.506G>A has a 60.9% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the PMS2 locus. See Shirts et al 2018, PMID 29887214.
Fulgent Genetics,Fulgent Genetics RCV000765966 SCV000897387 uncertain significance Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 4 2018-10-31 criteria provided, single submitter clinical testing

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