ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1556A>G (p.Tyr519Cys) (rs63750649)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001085962 SCV000166378 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000132386 SCV000187477 likely benign Hereditary cancer-predisposing syndrome 2018-09-15 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification;Other strong data supporting benign classification
Counsyl RCV000410304 SCV000488740 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2016-06-01 criteria provided, single submitter clinical testing
GeneDx RCV000483157 SCV000565411 uncertain significance not provided 2017-02-16 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1556A>G at the cDNA level, p.Tyr519Cys (Y519C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). PMS2 Tyr519Cys has been reported in at least two individuals with suspected Lynch syndrome, one of whom was also found to harbor a pathogenic MSH2 variant (Yurgelun 2015, Lagerstedt-Robinson 2016). It was also identified in an individual with an MSI-high, PMS2-deficient rectal cancer and a truncating PMS2 variant (Nomura 2015). However, the methodology used by Nomura et al. would not be able to distinguish whether Tyr519Cys was identified in PMS2 or its pseudogene, PMS2CL. This variant demonstrated efficient mismatch repair activity in comparison to a repair-deficient control in an in vitro functional assay (Drost 2013). Although this variant was observed in 1000 Genomes, population data in this region of PMS2 are not considered reliable due to high pseudogene homology. Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Tyr519Cys occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether PMS2 Tyr519Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Fulgent Genetics,Fulgent Genetics RCV000515260 SCV000611419 uncertain significance Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 4 2017-05-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000132386 SCV000910820 benign Hereditary cancer-predisposing syndrome 2015-12-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780619 SCV000918041 uncertain significance not specified 2018-03-12 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1556A>G (p.Tyr519Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 2.82 fold above the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Lynch Syndrome phenotype (0.00011), suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. In general, gnomAD data must be interpreted with caution due to the sequencing technology being unable to distinguish between PMS2 and its many overlapping pseudogenes. However, the variant is known to be specific to the PMS2 gene and is not found in the PMS2 pseudogenes, suggesting that the gnomAD frequencies are more likely to be reliable. The c.1556A>G variant has been reported in the literature in individuals affected with Lynch Syndrome (Nomura_2015, Lagerstedt-Robinson_2016, Yurgelun_2015). In two of these reported patients, the variant was found to co-occur with another pathogenic MMR variant (PMS2 - c.1492del11 [Nomura_2015]; MSH2 - c.2210+1G>A [Yurgelun_2015]), further supporting a benign impact for the variant. One publication reports experimental evidence evaluating mismatch repair activity, which showed very little effect of the variant on normal activity (Drost_2013). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (4 VUS and one likely benign). Based on the evidence outlined above, the variant was classified as VUS - possibly benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286033 SCV001472551 likely benign none provided 2019-12-23 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000483157 SCV001550130 likely benign not provided no assertion criteria provided clinical testing The PMS2 p.Tyr519Cys variant was identified in 10 of 2298 proband chromosomes (frequency: 0.004) from individuals or families with breast cancer or lynch syndrome (Balogh 2006, Lagerstedt-Robinson 2016, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs63750649) as “With Uncertain significance allele", ClinVar (classified as likely benign by Invitae and Ambry Genetics; as uncertain significance by Counsyl, GeneDx and Fulgent Genetics), Clinvitae, MutDB, Mismatch Repair Genes Variant Database, and in Insight Hereditary Tumors Database (3x, effect unknown). The variant was not identified in COGR, Cosmic, or Zhejiang University databases. The variant was identified in control databases in 24 of 277074 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 2 of 6464 chromosomes (freq: 0.0003), Latino in 11 of 34416 chromosomes (freq: 0.0003), European in 7 of 126622 chromosomes (freq: 0.0001), and South Asian in 4 of 30780 chromosomes (freq: 0.0001); it was not observed in the African, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Tyr519 residue is not conserved in mammals and four out of five 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 2 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. A functional in vitro study by Drost (2013) identified MMR activity of the variant in comparison to a negative control suggesting a neutral effect of the variant on protein function. In addition two patients identified with the c.1556A>G variant were also found to have a co-occurring pathogenic variant: MSH2, c.2210+1G>A and PMS2, c.1492del11, suggesting that the c.1556A>G variant may not be of clinical significance (Yurgelun 2015, Nomura 2015). 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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