Submissions for variant NM_000535.7(PMS2):c.1437C>G (p.His479Gln)

dbSNP: rs63750685

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001081746	SCV000166374	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000034615	SCV000171026	benign	not provided	2018-12-06	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27616075, 24728327, 28874130, 31433215, 31332305)
Ambry Genetics	RCV000162366	SCV000212673	benign	Hereditary cancer-predisposing syndrome	2018-04-09	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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000076809	SCV000266215	uncertain significance	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000121844	SCV000304718	benign	not specified		criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162366	SCV000691015	benign	Hereditary cancer-predisposing syndrome	2015-02-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034615	SCV000693232	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	PMS2: BP4, BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000034615	SCV000697296	benign	not provided	2017-08-09	criteria provided, single submitter	clinical testing	Variant summary: The PMS2 c.1437C>G (p.His479Gln) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a benign outcome. This was confirmed by a functional study that showed through an in vitro MMR assay that the H479Q mutant protein has significantly higher relative repair efficiency than repair-deficient control E705K (70 vs 10%, p<0.01) (Drost_2013). This variant was found in 1284/277610 control chromosomes (8 homozygotes) at a frequency of 0.0046252, which is approximately 41 times the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136), suggesting this variant is likely a benign polymorphism. Multiple publications have cited the variant in patients where it was often reported as a benign polymorphism. However, the frequency in ExAC and the cases reported in the literature may not be accurate due to the sequencing technology used being unable to distinguish between PMS2 and its overlapping pseudogenes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Also, in multiple internal LCA samples this variant was found to co-occur with other pathogenic variants: MSH2, c.942+3A>T, BRCA1, c.68_69delAG (p.Glu23fsX17), and BRCA2, c.5946delT (p.Ser1982fsX22). One study reports the variant in a sample that was IHC-negative for MLH1 and PMS2 and with observed MLH1 hypermethylation (van der Klift_2016). Taken together, this variant is classified as benign.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000625386	SCV000745193	benign	Lynch syndrome 4	2016-04-14	criteria provided, single submitter	clinical testing
Mendelics	RCV000076809	SCV000838178	likely benign	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000121844	SCV000860370	benign	not specified	2018-03-16	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034615	SCV000885989	benign	not provided	2023-06-20	criteria provided, single submitter	clinical testing
Mendelics	RCV000625386	SCV001137298	likely benign	Lynch syndrome 4	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000625386	SCV001322473	likely benign	Lynch syndrome 4	2018-03-13	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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Sema4, Sema4	RCV000162366	SCV002529794	benign	Hereditary cancer-predisposing syndrome	2020-08-18	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121844	SCV002550719	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149610	SCV003837734	benign	Breast and/or ovarian cancer	2021-06-08	criteria provided, single submitter	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153324	SCV003843502	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034615	SCV000043429	no known pathogenicity	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Benign.
ITMI	RCV000121844	SCV000086043	not provided	not specified	2013-09-19	no assertion provided	reference population
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000625386	SCV000745844	benign	Lynch syndrome 4	2015-11-08	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356193	SCV001551294	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PMS2 p.His479Gln variant was identified in 9 of 2670 proband chromosomes (frequency: 0.003) from individuals or families with CRC and MSI positive tumors (Johnston 2012, Basil 1999, Wang 1999, Berginc 2009). The variant was also identified in the following databases: dbSNP (ID: rs63750685) as “With Likely benign, Uncertain significance allele”, ClinVar (5x, as benign by GeneDx, Invitae, Ambry Genetics, Prevention Genetics, NIH, 2x, uncertain significance by InSight, University of Washington, 1x, with no classification by ITMI), Clinvitae (3x, as benign, 1x, as uncertain significance by ClinVar), Insight Colon Cancer Gene Variant Database (5x, as class 3), Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database (6x, as class 3). The variant was not identified in Cosmic, MutDB and Zhejiang Colon Cancer Databases. The variant was identified in control databases in 1281 of 277210 (8 homozygous) chromosomes at a frequency of 0.004621 in the following populations: African in 237 of 24026 chromosomes (freq. 0.010), other in 31 of 6466 chromosomes (freq. 0.005), Latino in 49 of 34420 chromosomes (freq. 0.0014), European in 488 of 126712 (4 homozygous) chromosomes (freq. 0.004), Ashkenazi Jewish in 76 of 10150 chromosomes (freq. 0.007), East Asian in 16 of 18866 chromosomes (freq. 0.0008), Finnish in 290 of 25794 chromosomes (freq. 0.011), and South Asian in 94 of 30776 (3 homozygous) chromosomes (freq. 0.003), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). A co-occurring pathogenic CHEK2 variant (c.1283C>T, p.Ser428Phe) is identified in 1 individual with breast cancer in our laboratory, increasing the likelihood that p.His479Gln variant does not have clinical significance. The p.His479Gln residue is not conserved in mammals and the variant amino acid Glutamine (Gln) is present in Chimpanzees, increasing the likelihood that this variant does not have clinical significance, 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. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000034615	SCV001798176	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000121844	SCV001905866	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000121844	SCV001920582	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000121844	SCV001955499	benign	not specified		no assertion criteria provided	clinical testing