ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1567T>A (p.Ser523Thr) (rs63751132)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656949 SCV000149570 uncertain significance not provided 2021-05-26 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32547938, 31391288, 31433215, 31159747, 26232782, 15470502, 28135145, 26689913, 27930734, 20186688, 26976419, 26845104, 24728327, 22290698, 17016615, 32095738, 31992580)
Ambry Genetics RCV000115661 SCV000187249 likely benign Hereditary cancer-predisposing syndrome 2018-11-28 criteria provided, single submitter clinical testing In silico models in agreement (benign);Structural Evidence
Invitae RCV001082540 SCV000254601 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-04 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000197412 SCV000266216 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000121851 SCV000601824 uncertain significance not specified 2016-09-19 criteria provided, single submitter clinical testing
Counsyl RCV000662627 SCV000785296 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2017-06-29 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000656949 SCV000806144 uncertain significance not provided 2015-12-01 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115661 SCV000822123 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115661 SCV000910645 likely benign Hereditary cancer-predisposing syndrome 2015-04-27 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000121851 SCV000918047 uncertain significance not specified 2019-06-06 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1567T>A (p.Ser523Thr) results in a conservative amino acid change located in the outside of any known functional domain or repeat of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251178 control chromosomes, predominantly at a frequency of 0.00046 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 4.0 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Lynch Syndrome phenotype (0.00011), however this data must be interpreted with caution as the sequencing techology utalized does not distinguish between PMS2 and highly homologous pseudogenes. c.1567T>A has been reported in the literature in individuals affected with Lynch Syndrome and other types of cancer (Nomura_2015, He_2016, Shirts_2016, Tung_2016, Yurgelun_2017, Lu_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (PMS2 c.1492del11; Nomura_2015), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (7 VUS, 2 likely benign). Based on the evidence outlined above, the variant was classified as VUS - possibly benign.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000656949 SCV001502551 uncertain significance not provided 2020-09-01 criteria provided, single submitter clinical testing
ITMI RCV000121851 SCV000086052 not provided not specified 2013-09-19 no assertion provided reference population
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357983 SCV001553600 likely benign Carcinoma of colon no assertion criteria provided clinical testing The PMS2 p.Ser523Thr variant was identified in 2 of 3900 proband chromosomes (frequency: 0.0005) from individuals or families with breast or colon cancer (Shirts 2015, Tung 2016). The variant was also identified in dbSNP (ID: rs63751132 as "With Uncertain significance allele"), ClinVar (2x as likely benign by Ambry Genetics and Invitae and 4x as uncertain significance by Counsyl, GeneDx, and two other clinical laboratories), Mismatch Repair Genes Variant Database, and InSiGHT Hereditary Tumors database. The variant was not identified in the COGR, Cosmic, MutDB, or Zhejiang University database. The variant was identified in control databases in 46 of 276928 chromosomes at a frequency of 0.0002, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 28 of 126528 chromosomes (freq: 0.0002), Other in 1 of 6464 chromosomes (freq: 0.0002), Latino in 1 of 34418 chromosomes (freq: 0.00003), Finnish in 2 of 25786 chromosomes (freq: 0.00008), and South Asian in 14 of 30782 chromosomes (freq: 0.0005); it was not observed in the African, Ashkenazi Jewish, or East Asian populations. The variant was identified by our lab in an individual with an MLH1/PMS2 deficient rectal tumour with a co-occurring pathogenic MLH1 variant (c.1790G>A, p.Trp597*), increasing the likelihood that the p.Ser523Thr variant does not have clinical significance. The variant was identified with a co-occurring pathogenic PMS2 (PMS2 c.1492del11; Nomura 2015), also increasing the likelihood that the p.Ser523Thr variant does not have clinical significance. The p.Ser523 residue is not conserved in mammals and 3 of 4 computational analyses (PolyPhen-2, SIFT, AlignGVGD, 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 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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