ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1280G>A (p.Arg427His) (rs112902065)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164844 SCV000215527 benign Hereditary cancer-predisposing syndrome 2016-11-08 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification;Subpopulation frequency in support of benign classification
Invitae RCV000206128 SCV000261586 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-10-27 criteria provided, single submitter clinical testing
GeneDx RCV000433523 SCV000514201 likely benign not specified 2017-01-04 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Color Health, Inc RCV000164844 SCV000902813 likely benign Hereditary cancer-predisposing syndrome 2016-05-22 criteria provided, single submitter clinical testing
Mendelics RCV000987833 SCV001137302 likely benign Hereditary nonpolyposis colorectal cancer type 4 2019-05-28 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358227 SCV001553901 likely benign not provided no assertion criteria provided clinical testing The PMS2 p.Arg427His variant was not identified in the literature. The variant was identified in dbSNP (ID: rs112902065) as "With Uncertain significance allele", and in ClinVar (classified as benign by Ambry Genetics, as likely benign by GeneDx and as uncertain significance by Invitae). The variant was identified in control databases in 17 of 276672 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 16 of 24004 chromosomes (freq: 0.0007), European in 1 of 126340 chromosomes (freq: 0.000008), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Arg427 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer,) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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