ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.532_534AAG[1] (p.Lys179del) (rs876661092)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000219855 SCV000279502 uncertain significance not provided 2015-10-13 criteria provided, single submitter clinical testing This in-frame deletion of 3 nucleotides in PMS2 is denoted c.535_537delAAG at the cDNA level and p.Lys179del (K179del) at the protein level. The normal sequence, with the bases that are deleted in braces, is TAAG[AAG]gtac. This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. This deletion of a single Lysine residue, the final residue, occurs at a position that is conserved across species and is located within the ATPase domain (Fukui 2011, Guarne 2001). Multiple splicing models predict that this variant may destroy the natural splice donor site for intron 6 and lead to abnormal splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Since in-frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider PMS2 Lys179del to be a variant of uncertain significance.
Invitae RCV000467401 SCV000552025 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-02-14 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides from exon 5 of the PMS2 mRNA (c.535_537delAAG). This leads to the deletion of 1 of 2 adjacent lysine residues in exon 5 of the PMS2 protein (p.Lys179del), but otherwise preserves the integrity of the reading frame. This sequence change affects a highly conserved nucleotide near the donor splice site, as it deletes the last 3 nucleotides of exon 5. However, the variant sequence at the 3' end of the exon 5 mRNA remains AAG. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 234572). According to multiple splice site algorithms, this particular variant is not predicted to significantly affect splicing. These predictions have not been confirmed by published functional studies. In summary, this variant is a novel in-frame deletion affecting the last three nucleotides of the PMS2 exon 5 mRNA. Although this change is not predicted to impact splicing and there is no indication that this variant causes disease, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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