ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1717A>T (p.Thr573Ser) (rs63751211)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163099 SCV000213608 likely benign Hereditary cancer-predisposing syndrome 2017-10-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other strong data supporting benign classification
CeGaT Praxis fuer Humangenetik Tuebingen RCV000512920 SCV000609248 uncertain significance not provided 2017-02-28 criteria provided, single submitter clinical testing
Color RCV000163099 SCV000902906 likely benign Hereditary cancer-predisposing syndrome 2015-12-09 criteria provided, single submitter clinical testing
Counsyl RCV000410142 SCV000488685 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2016-06-01 criteria provided, single submitter clinical testing
GeneDx RCV000512920 SCV000279219 uncertain significance not provided 2018-05-30 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1717A>T at the cDNA level, p.Thr573Ser (T573S) at the protein level, and results in the change of a Threonine to a Serine (ACC>TCC). This variant has been identified in at least two individuals with a personal history of a Lynch syndrome-associated cancer and/or colon polyps (Yurgelun 2015). Although this variant was observed in the Exome Sequencing Project, population data in this region of PMS2 are not considered reliable due to high pseudogene homology. Since Threonine and Serine share similar properties, this is considered a conservative amino acid substitution. PMS2 Thr573Ser occurs at a position that is not conserved and is not located in a known functional domain (Guarne 2001, Fukui 2011). Both in house in silico analyses and published computational models predict that this variant is unlikely to alter protein structure or function (Ali 2012). Based on currently available information, it is unclear whether PMS2 Thr573Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000163099 SCV000822124 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781750 SCV000920040 uncertain significance not specified 2018-04-18 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1717A>T (p.Thr573Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant of interest was observed with an allele frequency of 0.00006855 in 277164 control chromosomes (gnomAD). The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1-fold higher than the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Lynch Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. However, the technology used cannot detect the difference between the PMS2 and the pseudogene, therefore, these occurrences need to be cautiously considered. The variant, c.1717A>T, has been reported in the literature in individuals affected with Lynch Syndrome (Balough_2006, Tung_2015, Yurgelun_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. In addition, Tung_2015 reports the variant to co-occur with another potentially pathogenic MSH2 variant, c.842C>G (p.Ser281X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) predominantly cite the variant as "uncertain significance," although the most recent submission (Oct. 13, 2017) from a clinical diagnostic laboratory cites the variant as "likely benign." Based on the evidence outlined above, the variant was classified as VUS - possibly benign.
Invitae RCV000199342 SCV000254605 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-14 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 573 of the PMS2 protein (p.Thr573Ser). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and serine. This variant is present in population databases (rs63751211, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual with suspected Lynch syndrome (PMID: 25980754), as well as in individuals affected with breast and ovarian cancer (PMID: 17016615, 25186627). This variant is also known as c.1742A>T in the literature. ClinVar contains an entry for this variant (Variation ID: 183997). General algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and an algorithm developed specifically for mismatch repair genes (PMID: 22290698), suggest that this variant is likely to be tolerated. The serine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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