ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2182A>G (p.Thr728Ala) (rs141893001)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000567860 SCV000663438 benign Hereditary cancer-predisposing syndrome 2017-11-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance,In silico models in agreement (benign)
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000239355 SCV000296934 likely benign not specified 2015-07-27 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,VU University Medical Center Amsterdam RCV000625502 SCV000745836 benign Hereditary nonpolyposis colorectal cancer type 4 2016-12-11 no assertion criteria provided clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000239355 SCV000697337 uncertain significance not specified 2018-05-15 criteria provided, single submitter clinical testing Variant summary: PMS2 c.2182A>G (p.Thr728Ala) results in a non-conservative amino acid change located in the MutL C-terminal dimerisation domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0056 in 77206 control chromosomes, predominantly at a frequency of 0.056 within the African or African-American subpopulation in the ExAC database. The observed variant frequency within African or African-American control individuals in the ExAC database is approximately 493 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Lynch Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. However, the frequency in ExAC may not be accurate due to the sequencing technology used being unable to distinguish between PMS2 and its many overlapping pseudogenes. The variant, c.2182A>G, has been reported in the literature in one individual affected with Pancreatic Cancer (Hu_2015). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variants have been found in our database (PALB2 c.3323delA, p.Tyr1108fsX16; BRCA2 c.8970G>A, p.Trp2990X; BRCA2 c.1205delG, p.Gly402fsX2; PALB2 c.801_802dupTA, p.Lys268fsX12), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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 benign/likely benign. Since the occurrences of this variant in ExAC may be from the PMS2 pseudogene and the role of c.2182A>G in isolation is not clear, this variant was classified as VUS-possibly benign.
Invitae RCV000555261 SCV000625595 benign Hereditary nonpolyposis colon cancer 2018-01-04 criteria provided, single submitter clinical testing
Pathway Genomics RCV000172820 SCV000223786 uncertain significance Lynch syndrome I 2014-10-30 no assertion criteria provided clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000758628 SCV000887385 likely benign Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing PMS2 NM_000535.5:c.2182A>G has a 2.2% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.20 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the PMS2 locus. See Shirts et al 2018, PMID 29887214.

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