ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.230A>C (p.Glu77Ala) (rs777095030)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000477451 SCV000552072 uncertain significance Hereditary nonpolyposis colon cancer 2019-03-27 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 77 of the PMS2 protein (p.Glu77Ala). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is present in population databases (rs777095030, ExAC 0.05%), including one homozygous individual. This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 411085). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx RCV000481770 SCV000566627 uncertain significance not provided 2018-12-10 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.230A>C at the cDNA level, p.Glu77Ala (E77A) at the protein level, and results in the change of a Glutamic Acid to an Alanine (GAA>GCA). This variant has been reported in a pediatric patient with an unspecified tumor type (Chan 2018). PMS2 Glu77Ala was observed at an allele frequency of 0.06% (17/30782) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is located in the within 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 Glu77Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000776176 SCV000911288 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-09 criteria provided, single submitter clinical testing
Ambry Genetics RCV000776176 SCV001175963 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-25 criteria provided, single submitter clinical testing Insufficient evidence

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