Submissions for variant NM_000535.7(PMS2):c.1408C>T (p.Pro470Ser)

gnomAD frequency: 0.37107  dbSNP: rs1805321

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000030364	SCV000108294	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	MAF >1%
Eurofins Ntd Llc (ga)	RCV000079103	SCV000110972	benign	not specified	2018-04-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130721	SCV000185608	benign	Hereditary cancer-predisposing syndrome	2014-07-14	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 Diagnostics, LLC DBA Color Health	RCV000130721	SCV000292075	benign	Hereditary cancer-predisposing syndrome	2014-11-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000079103	SCV000304717	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000515612	SCV000469733	benign	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 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	RCV000034614	SCV000604897	benign	not provided	2023-11-30	criteria provided, single submitter	clinical testing
IntelligeneCG	RCV000515612	SCV000611718	benign	Lynch syndrome 4	2017-08-18	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000079103	SCV000711441	benign	not specified	2017-04-20	criteria provided, single submitter	clinical testing	p.Pro470Ser in Exon 11 of PMS2: This variant is not expected to have clinical si gnificance because it has been identified in 45% (4560/10152) of Ashkenazi Jewis h chromosomes and 41% (52732/126656) of European chromosomes by the Genome Aggre gation Database (GnomAD, http://gnomad.broadinstitute.org; dbSNP rs1805321).
Counsyl	RCV000515612	SCV000785318	benign	Lynch syndrome 4	2017-07-06	criteria provided, single submitter	clinical testing
Invitae	RCV001080458	SCV001000261	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000034614	SCV001845963	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24728327)
Genome-Nilou Lab	RCV001788997	SCV002031509	benign	Mismatch repair cancer syndrome 4	2021-10-25	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130721	SCV002529791	benign	Hereditary cancer-predisposing syndrome	2021-03-06	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000515612	SCV004016573	benign	Lynch syndrome 4	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000515612	SCV004043707	benign	Lynch syndrome 4	2023-05-10	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.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034614	SCV000043430	no known pathogenicity	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030364	SCV000053031	benign	Lynch syndrome	2011-06-22	no assertion criteria provided	clinical testing
ITMI	RCV000079103	SCV000086042	not provided	not specified	2013-09-19	no assertion provided	reference population
Pathway Genomics	RCV000144645	SCV000189972	benign	Lynch syndrome 1	2014-07-24	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353625	SCV000592934	benign	Endometrial carcinoma		no assertion criteria provided	clinical testing	The PMS2 p.Pro470Ser variant was identified in 464 of 1592 chromosomes (frequency: 0.294) from individuals with colorectal and/or endometrial cancer, suspected HNPCC and artherosclerosis (Borras_2013_2370975, Clendenning_2006_16619239, Gururangan_2008_17993636, He_2011_21984973, Hendriks_2006_16472587, Johnston_2012_22703879_supplementary, Kim_2004_15448003); however, control chromosomes were not analyzed in all of the studies, thus the prevalence of the variant in the general population could not be determined. The variant was also identified in dbSNP (ID: rs1805321) “With benign allele”, MutDB, and InSiGHT Colon Cancer DB. The variant was listed in the NHLBI Exome Sequencing Project in 3620 of 8600 European American alleles (frequency: 0.421) and in 1242 of 4856 African American alleles (frequency:0.256), increasing the likelihood that it may be a polymorphism in certain populations. The p.Pro470Ser variant is not conserved/conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. This variant is unlikely to have an effect on splicing as it is downstream of the exon/intron junction. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000079103	SCV000691974	benign	not specified		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000079103	SCV001744259	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000079103	SCV001906094	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000079103	SCV001922389	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000079103	SCV001951485	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000079103	SCV001971498	benign	not specified		no assertion criteria provided	clinical testing