ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.123_131del (p.Leu42_Glu44del) (rs863224676)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000196505 SCV000254595 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-01-08 criteria provided, single submitter clinical testing This variant, c.123_131delGTTAGTAGA, results in the deletion of 3 amino acids of the PMS2 protein (p.Leu42_Glu44del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with suspected Lynch syndrome and constitutive mismatch repair deficiency syndrome (PMID: 25980754, 30653781). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 216449). This variant has been reported to affect PMS2 protein function (PMID: 30653781). Different missense variants affecting amino acid residues adjacent to this deletion (p.Glu41Ala and p.Asn45Thr) have been reported in individuals affected with colorectal cancer and constitutional mismatch repair deficiency (PMID: 24027009, 23709753, 24440087), indicating that this region of the protein may be critical for proper protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx RCV000216484 SCV000279515 likely pathogenic not provided 2018-03-23 criteria provided, single submitter clinical testing This in-frame deletion of nine nucleotides in PMS2 is denoted c.123_131delGTTAGTAGA at the cDNA level and p.Leu42_Glu44del (L42_E44del) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AGGA[delGTTAGTAGA]AAAC. This deletion includes residues that are conserved across species (Leu42 and Glu44) and a third (Val43) where amino acids with properties similar to Valine are tolerated across species, and is located in the ATP binding motif 1 of the ATPase domain (Guarne 2001). This variant, also published as PMS2 c.123_131del, was observed in an individual undergoing multigene panel testing due to a personal history of a Lynch syndrome-related cancer and/or polyps (Yurgelun 2015). Of note, an adjacent missense variant, PMS2 Ser46Ile, which is located within the same ATP-binding motif, has been observed in several individuals with Lynch syndrome-associated tumors with absence of PMS2 observed via IHC, in several individuals with congenital mismatch repair deficiency (CMMR-D), and has been shown to result in deficient mismatch repair activity (Senter 2008, Drost 2013, ten Broeke 2015, Heath 2016). We consider PMS2 c.123_131delGTTAGTAGA to be likely pathogenic.
Ambry Genetics RCV000561780 SCV000663563 likely pathogenic Hereditary cancer-predisposing syndrome 2019-07-08 criteria provided, single submitter clinical testing Insufficient evidence;Structural Evidence;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Other data supporting pathogenic classification
Counsyl RCV000663087 SCV000786178 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2018-03-13 criteria provided, single submitter clinical testing
Color RCV000561780 SCV001341146 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001251273 SCV001426799 likely pathogenic Hereditary nonpolyposis colon cancer 2020-07-16 criteria provided, single submitter clinical testing Variant summary: PMS2 c.123_131delGTTAGTAGA (p.Leu42_Glu44del) results in an in-frame deletion that is predicted to remove three amino acids from highly conserved alpha-helix in ATPase domain of the encoded protein (DArcy_2019). The variant was absent in 245774 control chromosomes (gnomAD). c.123_131delGTTAGTAGA has been reported in the literature in one individual affected with one individual who had a history of Lynch syndrome associated cancer and/or polyps (Yurgelun_2015). DArcy_2019 reported this variant has been observed in one unaffected proband whose offspring was clinically diagnosed with constitutive mismatch repair deficiency syndrome (CMMRD). However, this CMMRD patient inherited a known PMS2 pathogenic mutation. In DArcy_2019, in vitro study reports this variant affects PMS2 protein function based on decreasing in MMR capacity and ATPase activity and structural data revealed that the protein product is grossly misfolded and aggregated. These data indicate that the variant is very likely to be associated with disease. Moreover, different missense variants ( p.E41A, p.N45T, p.S46N, p.S46I) residue adjacent to this deletion have been reported in individuals affected with colorectal cancer and constitutional mismatch repair deficiency in HGMD, indicating that this region of the protein may be critical for proper protein function. Five ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic (3x) and uncertain significance (2x). Based on the evidence outlined above, the variant was classified as likely pathogenic.

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