ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.355G>A (p.Asp119Asn) (rs587781913)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000552145 SCV000625646 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-18 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 119 of the PMS2 protein (p.Asp119Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs587781913, ExAC 0.001%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 455716). 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 tolerated, 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.
Integrated Genetics/Laboratory Corporation of America RCV000589176 SCV000697365 uncertain significance not specified 2019-09-20 criteria provided, single submitter clinical testing Variant summary: PMS2 c.355G>A (p.Asp119Asn) results in a conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain (IPR002099) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. In addition, the variant is located close to a canonical splice site and therefore could affect mRNA splicing: 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251140 control chromosomes (gnomAD). This observation needs to be cautiously considered due to the possibility of the PMS2 pseudogene being captured. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.355G>A in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color RCV000776344 SCV000911704 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV000776344 SCV001182112 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-18 criteria provided, single submitter clinical testing Insufficient evidence

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