ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1437C>G (p.His479Gln) (rs63750685)

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Total submissions: 22
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001081746 SCV000166374 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-04 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 In silico models in agreement (benign);Other data supporting benign classification;Other strong data supporting benign classification
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,PreventionGenetics RCV000121844 SCV000304718 benign not specified criteria provided, single submitter clinical testing
Color Health, Inc RCV000162366 SCV000691015 benign Hereditary cancer-predisposing syndrome 2015-02-19 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034615 SCV000693232 likely benign not provided 2021-03-01 criteria provided, single submitter clinical testing
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 Hereditary nonpolyposis colorectal cancer type 4 2016-04-14 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000625386 SCV000745844 benign Hereditary nonpolyposis colorectal cancer type 4 2015-11-08 criteria provided, single submitter clinical testing
Mendelics RCV000076809 SCV000838178 likely benign Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000121844 SCV000860370 benign not specified 2018-03-16 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282359 SCV000885989 benign none provided 2020-07-20 criteria provided, single submitter clinical testing
Mendelics RCV000625386 SCV001137298 likely benign Hereditary nonpolyposis colorectal cancer type 4 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000625386 SCV001322473 likely benign Hereditary nonpolyposis colorectal cancer type 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.
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
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
Human Genetics - Radboudumc,Radboudumc RCV000121844 SCV001955499 benign not specified no assertion criteria provided clinical testing

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