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

dbSNP: rs863224676

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000196505	SCV000254595	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-08	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 (gnomAD no frequency). This variant has been observed in individual(s) with Lynch syndrome and constitutive mismatch repair deficiency syndrome (PMID: 25980754, 30653781; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 216449). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects PMS2 function (PMID: 30653781). 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	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-17	criteria provided, single submitter	clinical testing	The c.123_131delGTTAGTAGA pathogenic mutation (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 three amino acids between codons 42 and 44. This alteration has been identified in three unrelated individuals with colorectal tumors that demonstrated isolated loss of PMS2 expression by IHC; two of these 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 cohort of healthy individuals undergoing population screening for genetic conditions (Grzymski JJ et al. Nature Med. 2020 Aug;26(8):1235-9). However, it was also identified in a patient with Constitutional Mismatch Repair Deficiency syndrome (CMMRD), who also had PMS2 mutation p.R802* in trans (D'Arcy BM et al. Hum. Mutat. 2019 Apr;40:458-471). D'Arcy et al. also 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 is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Counsyl	RCV000663087	SCV000786178	uncertain significance	Lynch syndrome 4	2018-03-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000561780	SCV001341146	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-05-23	criteria provided, single submitter	clinical testing	This variant is a 3 amino acid deletion within the amino-terminal ATPase domain of the PMS2 protein. Functional studies have shown that this variant is defective for protein expression, mismatch repair activity and ATPase activity, and demonstrated increased microsatellite instability (PMID: 30653781, 35189042). Structural studies have also indicated the variant protein is disordered and prone to aggregation (PMID: 30653781). This variant has been reported in several individuals affected with Lynch syndrome-associated cancers (PMID: 25980754; ClinVar SCV000663563.3). This variant has also been observed in compound heterozygous state with a known pathogenic PMS2 variant in an individual affected with autosomal recessive constitutional mismatch repair disorder (PMID: 30653781). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
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.