ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.241G>A (p.Glu81Lys) (rs730881919)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160904 SCV000211600 uncertain significance not provided 2018-10-18 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.241G>A at the cDNA level, p.Glu81Lys (E81K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant has been observed in at least one individual with endometrial cancer and in at least two individuals with breast and/or ovarian cancer, though one of the latter individuals also carried a pathogenic PALB2 variant (Goodfellow 2015, Cock-Rada 2018). PMS2 Glu81Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the ATPase domain (Guarne 2001). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PMS2 Glu81Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000206458 SCV000260529 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 81 of the PMS2 protein (p.Glu81Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs730881919, ExAC 0.009%). This variant has been reported in individuals affected with endometrial cancer or breast and/or ovarian cancer, one of whom was also found to have a pathogenic allele in PALB2 (PMID: 26552419, 28528518). ClinVar contains an entry for this variant (Variation ID: 182817). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Ambry Genetics RCV000575606 SCV000663434 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-06 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000575606 SCV000691061 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-19 criteria provided, single submitter clinical testing
Counsyl RCV000662544 SCV000785124 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2017-05-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781760 SCV000920058 uncertain significance not specified 2018-12-18 criteria provided, single submitter clinical testing Variant summary: PMS2 c.241G>A (p.Glu81Lys) results in a conservative amino acid change located in the DNA mismatch repair protein family, N-terminal and Histidine kinase/HSP90-like ATPase domains of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 245818 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.241G>A, has been reported in the literature in individuals affected with HBOC (Cock-Rada_2017, Goodfellow_2015). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (PALB2 c.1240C>T, p.Arg414X), providing supporting evidence for a benign role. In addition, one patient was indicated to have IHC defects consistent with an MSH2 mutation (absent MSH2 and MSH6)(Goodfellow_2015)To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160904 SCV001134593 uncertain significance not provided 2018-11-02 criteria provided, single submitter clinical testing

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