ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.354C>T (p.Ser118=) (rs760615315)

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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 RCV000165593 SCV000216327 likely benign Hereditary cancer-predisposing syndrome 2014-09-24 criteria provided, single submitter clinical testing
Color RCV000165593 SCV000686195 likely benign Hereditary cancer-predisposing syndrome 2016-09-20 criteria provided, single submitter clinical testing
GeneDx RCV000603379 SCV000732676 likely benign not specified 2018-02-01 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.
Integrated Genetics/Laboratory Corporation of America RCV000587468 SCV000697364 uncertain significance not provided 2017-07-28 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.354C>T (p.Ser118Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. The variant of interest has not been found in a large, broad control population, ExAC in 121406 control chromosomes and was found in gnomAD in 3/276900 control chromosomes at a frequency of 0.00001083, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant of 0.0001136. In addition, one clinical diagnostic laboratory classified this variant as likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS).
Invitae RCV000630377 SCV000751333 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-20 criteria provided, single submitter clinical testing This sequence change affects codon 118 of the PMS2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PMS2 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 186067). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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.

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