ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.857A>G (p.Asp286Gly) (rs116788608)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588331 SCV000149615 uncertain significance not provided 2018-08-08 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.857A>G at the cDNA level, p.Asp286Gly (D286G) at the protein level, and results in the change of an Aspartic Acid to a Glycine (GAC>GGC). This variant was observed in an individual with a Lynch syndrome-associated tumor and/or colon polyps (Yurgelun 2015) and co-occurred with a truncating MSH6 variant in an individual with ovarian and endometrial cancer (J?ri 2015). PMS2 Asp286Gly was also observed in individuals with ovarian or breast cancer, as well as in 1/50 healthy Central Asian individuals undergoing whole genome sequencing (Bodian 2014, Lu 2015, Rummel 2017). Of note, the participants in the Bodian et al. study were younger than 50 years old thus the unaffected status of this individual may not be significant. PMS2 Asp286Gly was observed at an allele frequency of 0.02% (25/126666) in individuals of European ancestry in large population cohorts (Lek 2016). PMS2 Asp286Gly is located in the ATPase domain (Guarne 2001). In silico analysis, including protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PMS2 Asp286Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115706 SCV000216880 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-04 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000197094 SCV000254618 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-26 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 286 of the PMS2 protein (p.Asp286Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs116788608, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individual(s) with suspected Lynch syndrome, ovarian cancer, and pancreatic cancer (PMID: 25980754, 26517685, 26689913, 28726808). However, in one of these individuals a pathogenic allele was identified in the MSH6 gene, which suggests that this c.857A>G substitution in PMS2 was not the primary cause of disease (PMID: 26517685). ClinVar contains an entry for this variant (Variation ID: 127798). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). 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.
Counsyl RCV000409948 SCV000488997 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2016-08-02 criteria provided, single submitter clinical testing
Color RCV000115706 SCV000686246 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000121861 SCV000697393 uncertain significance not specified 2019-09-04 criteria provided, single submitter clinical testing Variant summary: PMS2 c.857A>G (p.Asp286Gly) results in a non-conservative amino acid change located in the N-terminal domain (IPR002099) within the S5 domain 2-like fold (IPR013507) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 282838 control chromosomes, within the Non-Finnish European subpopulation predominantly at a frequency of 0.0002 in the gnomAD database. Although the observed variant frequency within Non-Finnish European control individuals is approximately 1.76 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Lynch Syndrome (LS) phenotype (0.00011), the technology utilized for this data set does not rule out pseudogene interference and thus might not allow unequivocal conclusions about variant significance. c.857A>G has been reported in the literature in at least one individual affected with (suspected) Lynch Syndrome (Yurgelun_2015), and in other individuals affected with various neoplasms, including endometrial and ovarian- (Jori_2016), breast- (Rummel_2017) and pancreatic cancer (Chaffee_2018), as well as in a pediatric patient affected with acute myeloid leukemia (McNeer_2019). In one of these cases a co-occurrence with a pathogenic variant has been reported (MSH6 c.2569_2572del, p.Asp857Phefs10*; Jori_2016), providing supporting evidence for a benign role. These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight other clinical laboratories have submitted assessments for this variant to ClinVar (evaluation after 2014) and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics RCV000708992 SCV000838189 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588331 SCV000888418 uncertain significance not provided 2017-10-16 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765960 SCV000897381 uncertain significance Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 4 2018-10-31 criteria provided, single submitter clinical testing
ITMI RCV000121861 SCV000086063 not provided not specified 2013-09-19 no assertion provided reference population
Pathway Genomics RCV000144656 SCV000189983 uncertain significance Lynch syndrome I 2014-07-24 no assertion criteria provided clinical testing

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