Submissions for variant NM_000535.7(PMS2):c.1454C>A (p.Thr485Lys) (rs1805323)

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076810	SCV000108296	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	MAF >1%
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000079104	SCV000110973	benign	not specified	2018-03-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130906	SCV000185815	benign	Hereditary cancer-predisposing syndrome	2014-07-31	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Color Health, Inc	RCV000130906	SCV000292094	benign	Hereditary cancer-predisposing syndrome	2014-11-04	criteria provided, single submitter	clinical testing
PreventionGenetics,PreventionGenetics	RCV000079104	SCV000304719	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000625385	SCV000469732	benign	Hereditary nonpolyposis colorectal cancer type 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV001282358	SCV000604896	benign	none provided	2020-08-11	criteria provided, single submitter	clinical testing
Invitae	RCV001081087	SCV000625528	benign	Hereditary nonpolyposis colorectal neoplasms	2020-12-08	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000079104	SCV000711442	benign	not specified	2017-04-20	criteria provided, single submitter	clinical testing	p.Thr485Lys in exon 11 of PMS2: This variant is not expected to have clinical si gnificance because it has been identified in 35% (3077/8632) of East Asian chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs1805323).
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000625385	SCV000745192	benign	Hereditary nonpolyposis colorectal cancer type 4	2017-05-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000625385	SCV000785345	benign	Hereditary nonpolyposis colorectal cancer type 4	2017-07-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000034616	SCV001899117	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28932927, 28347324, 24728327)
Biesecker Lab/Clinical Genomics Section,National Institutes of Health	RCV000034616	SCV000043428	no known pathogenicity	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Benign.
ITMI	RCV000079104	SCV000086044	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV001353499	SCV000592935	benign	Endometrial carcinoma		no assertion criteria provided	clinical testing	PMS2, EXON11, c.1454C>A, p. Thr485Lys, Benign (ACMG 5) The c.1454C>A variant was identified in 7 of 338 chromosomes (frequency: 0.021) from individuals or families with HNPCC and Lynch Syndrome exhibiting café-au-lait spots and cancer. (14756672_Thompson_2004, 15256438_Nakagawa_2004, 16472587_Hendriks_2006, 16619239_Clenndening_2006, 17993636_Gururangan_2008, 24027009_Drost_2013) The variant was also identified in dbSNP (ID: rs1805323 ) “With benign allele”, with a minor allele frequency of 0.112(1000 Genomes Project) HGMD, COSMIC, “Mismatch Repair Genes Variant Database”, “InSiGHT Colon Cancer Database”, ClinVar database as a benign variant by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports). The variant was classified as “unclassified” by a clinical laboratory within the Canadian Open Genetics Repository (http://opengenetics.ca/). This variant was identified in the 1000 Genomes Project in 247 of 2178 chromosomes (frequency: 0.113), and in Exome Variant Server project in 350 of 8600 (frequency: 0.041) European American and in 86 of 4406 (frequency: 0.019) African American alleles, increasing the likelihood that this is/may be a low frequency benign variant in certain populations of origin. This variant was identified in the Exome Aggregation Consortium database to have an allele frequency of 0.079. The p.Thr485Lys variant is not expected to have clinical significance because it is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Thr485 residue is not conserved in mammals and the variant amino acid Threonine (Thr) is present in Macaques, increasing the likelihood that this variant does not have clinical significance. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000079104	SCV000691973	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute	RCV000079104	SCV001906413	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics,Academic Medical Center	RCV000079104	SCV001924426	benign	not specified		no assertion criteria provided	clinical testing