Submissions for variant NM_000535.7(PMS2):c.1560G>A (p.Ala520=)

gnomAD frequency: 0.00039  dbSNP: rs201167814

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000127461	SCV000171028	benign	not specified	2014-01-22	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000162432	SCV000212779	likely benign	Hereditary cancer-predisposing syndrome	2014-05-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV001079708	SCV000253288	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162432	SCV000537477	likely benign	Hereditary cancer-predisposing syndrome	2015-06-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000487654	SCV000575509	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	PMS2: BP4, BP7
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000487654	SCV000697302	benign	not provided	2017-06-26	criteria provided, single submitter	clinical testing	Variant summary: The c.1560G>A (p.Ala520=) in PMS2 gene is a synonymous change that involves a non-conserved nucleotide. 4/5 programs in Alamut predict that this variant does not affect the normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population datasets of ExAC and gnomAD at a similar frequencies 0.00033 (38/120402 and 93/277018 chrs tested, respectively), which is about 3 times of the maximum expected allele frequency for a pathogenic PMS2 variant (0.00011). Sequence allignment and reads in ExAC support that the minor alleles reported in ExAC are not from the pseudogene. The variant has not, to our knowledge, been reported in affected individuals via published reports but is cited as Benign/Likely Benign by reputable databases/clinical laboratories. Taking together, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000487654	SCV000888395	benign	not provided	2023-05-12	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001159293	SCV001320993	uncertain significance	Lynch syndrome 4	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798425	SCV002042787	likely benign	Breast and/or ovarian cancer	2023-06-22	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000127461	SCV002072391	likely benign	not specified	2019-04-05	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162432	SCV002530203	likely benign	Hereditary cancer-predisposing syndrome	2021-04-11	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000127461	SCV002550712	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000487654	SCV004563196	likely benign	not provided	2023-11-09	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000162432	SCV000788106	likely benign	Hereditary cancer-predisposing syndrome	2017-09-27	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357279	SCV001552699	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PMS2 p.Ala520= variant was not identified in the literature nor was it identified in the following databases: COGR, Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs201167814) “With Uncertain significance allele”, ClinVar (classified benign by GeneDx, likely benign by Ambry Genetics, Invitae, Color Genomics Inc, Quest Diagnostics Nichols Institute San Juan Capistrano, and uncertain significance by Praxis fuer Humangenetik Tuebingen), Clinvitae (4x), and in control databases in 93 of 277018 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 23986 chromosomes (freq: 0.00004), “Other” in 2 of 6464 chromosomes (freq: 0.0003), Latino in 16 of 34418 chromosomes (freq: 0.0005), European Non-Finnish in 66 of 126586 chromosomes (freq: 0.0005), East Asian in 4 of 18864 chromosomes (freq: 0.0002), European Finnish in 2 of 25782 chromosomes (freq: 0.00008), and South Asian in 2 of 30782 chromosomes (freq: 0.00007); it was not observed in the Ashkenazi Jewish population. The p.Ala520= variant is not expected to have clinical significance because it does not result in a change of amino acid. This variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000487654	SCV001955641	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000487654	SCV001966853	likely benign	not provided		no assertion criteria provided	clinical testing