ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1096G>C (p.Asp366His) (rs141769057)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586764 SCV000149558 uncertain significance not provided 2018-01-03 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1096G>C at the cDNA level, p.Asp366His (D366H) at the protein level, and results in the change of an Aspartic Acid to a Histidine (GAT>CAT). This variant has been reported at least one individual with early-onset breast cancer with previously negative BRCA1/2 analysis (Maxwell 2015). PMS2 Asp366His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether PMS2 Asp366His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV001085405 SCV000254593 likely benign Hereditary nonpolyposis colon cancer 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000220170 SCV000273033 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-29 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000115649 SCV000601806 uncertain significance not specified 2017-05-04 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586764 SCV000697278 uncertain significance not provided 2016-11-25 criteria provided, single submitter clinical testing Variant summary: The c.1096G>C (p.Asp366His) in PMS2 gene is a missense change that involves a conserved nucleotide and 3/5 in silico tools predict benign outcome. The variant of interest is located outside of any know domain; however, the functional impact of this missense change is yet to be studied. The variant is present in the large control population dataset of ExAC at a frequency 0.000016 (2/121688chrs tested), which does not exceed the estimated maximal expected allele frequency of a pathogenic variant (0.0001). The variant has been reported in at least 1 affected individual without strong evidence for causality. In addition, several reputable databases/clinical laboratories and published reports cite the variant as VUS (Maxwell, 2014; Amendola, 2016). At this time there is not sufficient undeniable evidence to classify this variant with confidence. Taken together, the variant was classified as VUS until more data becomes available.
CSER _CC_NCGL, University of Washington RCV000590932 SCV000700133 uncertain significance Lynch syndrome 2016-10-01 criteria provided, single submitter research Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 30 year old male diagnosed with colon cancer at age 30. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000115649 SCV000711440 uncertain significance not specified 2017-04-03 criteria provided, single submitter clinical testing The p.Asp366His variant in PMS2 has been previously identified in at least 1 in dividual with early onset breast cancer who had tested negative for variants in BRCA1 and 2 (Maxwell 2015). This variant has also been identified in 1/8654 of E ast Asian chromosomes and 1/11578 of Latino chromosomes by the Exome Aggregation Consortium (ExAC,; dbSNP rs141769057). Asparagin e (Asp) at position 366 is not conserved in mammals or evolutionarily distant sp ecies and the change to histidine (His) is present in 2 turtle species, suggesti ng this change may be tolerated. Additional computational prediction tools do no t provide strong support for or against an impact to the protein. In summary, th e clinical significance of the p.Asp366His variant is uncertain.
Color RCV000220170 SCV000902928 likely benign Hereditary cancer-predisposing syndrome 2016-02-29 criteria provided, single submitter clinical testing

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