Submissions for variant NM_000535.7(PMS2):c.2324A>G (p.Asn775Ser)

gnomAD frequency: 0.00025  dbSNP: rs17420802

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000030368	SCV000108343	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	MAF >1%
Eurofins Ntd Llc (ga)	RCV000079108	SCV000110977	benign	not specified	2018-03-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001705609	SCV000171039	benign	not provided	2018-12-06	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22949387, 24728327, 22594646, 28347324)
Ambry Genetics	RCV000130364	SCV000185216	benign	Hereditary cancer-predisposing syndrome	2014-07-23	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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	RCV000755368	SCV000252717	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000079108	SCV000304729	benign	not specified		criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001705609	SCV000604892	benign	not provided	2023-10-23	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000615735	SCV000745184	benign	Lynch syndrome 4	2017-05-31	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000615735	SCV000745835	benign	Lynch syndrome 4	2016-01-22	criteria provided, single submitter	clinical testing
Counsyl	RCV000615735	SCV000785258	benign	Lynch syndrome 4	2017-06-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000755648	SCV000883047	likely benign	Mismatch repair cancer syndrome 1; Lynch syndrome 4	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000615735	SCV001322355	benign	Lynch syndrome 4	2019-07-18	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798022	SCV002042799	likely benign	Breast and/or ovarian cancer	2022-09-13	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130364	SCV002530290	likely benign	Hereditary cancer-predisposing syndrome	2021-04-27	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000079108	SCV002550685	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000615735	SCV004044366	benign	Lynch syndrome 4	2023-05-11	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
CeGaT Center for Human Genetics Tuebingen	RCV001705609	SCV004163705	likely benign	not provided	2023-06-01	criteria provided, single submitter	clinical testing	PMS2: PP2, BS2
Color Diagnostics, LLC DBA Color Health	RCV000130364	SCV004359015	benign	Hereditary cancer-predisposing syndrome	2014-12-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030368	SCV000053035	benign	Lynch syndrome	2013-02-18	no assertion criteria provided	clinical testing
ITMI	RCV000079108	SCV000086053	not provided	not specified	2013-09-19	no assertion provided	reference population
Pathway Genomics	RCV000144644	SCV000189971	benign	Lynch syndrome 1	2014-07-24	no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000079108	SCV000257310	benign	not specified		no assertion criteria provided	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000030368	SCV000296935	uncertain significance	Lynch syndrome	2015-10-30	flagged submission	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353478	SCV000592950	benign	Endometrial carcinoma		no assertion criteria provided	clinical testing	PMS2, Exon14, c.2324A>G, p. Asn775Ser, Benign, ACMG 5 The c.2324A>G variant was identified in 32 of 1428 proband chromosomes (frequency: 0.022) from individuals or families with HNPCC or Lynch syndrome (20698049_sheng_2010, 14756672_Thompson_2004, Clendenning_2006_16619239); however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. The variant was also identified in dbSNP (ID: rs17420802 ) “With benign allele”, HGMD, COSMIC, “Mismatch Repair Genes Variant Database”, “InSiGHT Colon Cancer Database”, and the ClinVar database by 7 submitters as benign. The p.Asn775 residue is conserved across mammals and lower organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Asn775Ser variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. The c.2324A>G variant occurs outside of the splicing consensus sequence and in silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) does not predict a difference in splicing in 5 of 5 different programs. (However, this information is not predictive enough to rule out pathogenicity.) In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000615735	SCV000734559	benign	Lynch syndrome 4		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001705609	SCV001922142	likely benign	not provided		no assertion criteria provided	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000130364	SCV001977060	likely benign	Hereditary cancer-predisposing syndrome	2021-09-27	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000079108	SCV002036003	benign	not specified		no assertion criteria provided	clinical testing