ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.353+6A>G (rs376449640)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000226224 SCV000285130 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-11 criteria provided, single submitter clinical testing This sequence change falls in intron 4 of the PMS2 gene. It does not directly change the encoded amino acid sequence of the PMS2 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs376449640, ExAC 0.01%). This variant has been observed in an individual affected with colorectal cancer (PMID: 28135145). It is also known as IVS4+6A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 237913). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000507750 SCV000601849 uncertain significance not specified 2017-04-10 criteria provided, single submitter clinical testing
Color RCV000581327 SCV000691068 likely benign Hereditary cancer-predisposing syndrome 2016-04-29 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586664 SCV000697361 uncertain significance not provided 2016-10-21 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.353+6A>G variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a disease-causing outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 7/112962 control chromosomes at a frequency of 0.000062, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). In addition, one clinical diagnostic laboratory has classified this variant as uncertain significance. 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) until additional information becomes available.
Counsyl RCV000663107 SCV000786224 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2018-03-23 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000586664 SCV000806215 likely benign not provided 2017-08-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586664 SCV000888415 uncertain significance not provided 2018-03-02 criteria provided, single submitter clinical testing

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