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 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-10-21 criteria provided, single submitter clinical testing This variant, c.123_131del, results in the deletion of 3 amino acid(s) 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, Invitae). 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. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000216484 SCV000279515 pathogenic not provided 2020-03-10 criteria provided, single submitter clinical testing In-frame deletion of 3 amino acids in a non-repeat region predicted to critically alter the protein.; Published functional studies demonstrate a damaging effect: deficient mismatch repair activity, reduced protein expression, and absent ATPase activity (DArcy 2019); Observed in individuals with Lynch-associated cancer and/or polyps (Yurgelun 2015); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30653781, 25980754, 32719484)
Ambry Genetics RCV000561780 SCV000663563 likely pathogenic Hereditary cancer-predisposing syndrome 2020-02-25 criteria provided, single submitter clinical testing The c.123_131delGTTAGTAGA variant (also known as p.L42_E44del) is located in coding exon 2 of the PMS2 gene. This variant results from an in-frame deletion of 9 nucleotides at positions 123 to 131. This results in the deletion of 3 amino acids between codons 42 and 44. This alteration was identified in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps. (Yurgelun MB et al. Gastroenterology. 2015 Sep;149:604-13.e20). This alteration was also identified in three unrelated individuals with colorectal tumors that demonstrated isolated loss of PMS2 expression on IHC and two probands had a family history of colorectal cancer (Ambry internal data). Based on an internal structural assessment, this alteration disrupts critical ATP-binding residues (Ban C et al. Cell. 1999 Apr;97:85-97; Guarné A et al. EMBO J. 2001 Oct;20:5521-31; Wu H et al. Acta Crystallogr F Struct Biol Commun. 2015 Aug;71:981-5). This variant has been reported in a patient with Constitutional Mismatch Repair Deficiency syndrome (CMMRD), who also had PMS2 p.R802* in trans (D'Arcy BM et al. Hum. Mutat. 2019 Apr;40:458-471). D'Arcy et al. demonstrated that this variant lacks in vitro mismatch repair and ATPase activities. These amino acid positions are well conserved in available vertebrate species. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature. 2016 08;536:285-91). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012;7:e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Counsyl RCV000663087 SCV000786178 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2018-03-13 criteria provided, single submitter clinical testing
Color Health, Inc RCV000561780 SCV001341146 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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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