ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.88C>T (p.Gln30Ter) (rs141577476)

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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 RCV000131992 SCV000187050 pathogenic Hereditary cancer-predisposing syndrome 2018-01-08 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000684779 SCV000552069 pathogenic Hereditary nonpolyposis colon cancer 2019-11-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln30*) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in the literature in an individual with endometrial and ovarian cancer (PMID: 25856668). ClinVar contains an entry for this variant (Variation ID: 142650). Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000521392 SCV000621341 pathogenic not provided 2017-10-06 criteria provided, single submitter clinical testing The Q30X variant in the PMS2 gene has been reported previously in individuals with endometrial and/or ovarian cancer (Goodenberger et al., 2016). At least one tumor showed absence of PMS2 via mismatch repair immunohistochemistry (Goodenberger et al., 2016). The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. The Q30X variant is not observed in large population cohorts (Lek et al., 2016). Loss-of-function variants are known to be pathogenic in this gene associated with Lynch syndrome. Therefore, based on the ACMG recommendations, Q30X is interpreted as an expected pathogenic sequence change.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000475400 SCV000712559 pathogenic Lynch syndrome 2016-11-16 criteria provided, single submitter clinical testing The p.Gln30X variant in PMS2 has been reported in 2 individuals with Lynch syndr ome-associated cancers (Goodenberger 2015), and was absent from large population studies. This nonsense variant leads to a premature termination codon at positi on 30, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the PMS2 gene is an established disease mechanism in Lynch Syndrome. In summary, this variant meets criteria to be classified as pathogenic for Lynch Syndrome in an autosomal dominant manner.
Color RCV000131992 SCV000905476 pathogenic Hereditary cancer-predisposing syndrome 2018-03-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001175479 SCV001339068 pathogenic Hereditary nonpolyposis colon cancer 2020-03-06 criteria provided, single submitter clinical testing Variant summary: PMS2 c.88C>T (p.Gln30X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 245770 control chromosomes. c.88C>T has been reported in the literature in individuals affected with endometrial and/or ovarian cancer (Goodenberger_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197302 SCV001367965 pathogenic Epicanthus; Hypertelorism; Clinodactyly of the 5th finger; Downslanted palpebral fissures; Single transverse palmar crease; Long philtrum; Sandal gap; Muscular hypotonia 2019-05-06 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3. This variant was detected in hemizygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001199055 SCV001370050 pathogenic Colon cancer 2019-01-03 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1PM2inPP4. This variant was detected in homozygous state.

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