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
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
Invitae RCV000555261 SCV000625595 benign not provided 2019-03-05 criteria provided, single submitter clinical testing
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)
Integrated Genetics/Laboratory Corporation of America RCV000239355 SCV000697337 likely benign not specified 2019-05-28 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 0.002 in 229692 control chromosomes, predominantly at a frequency of 0.029 within the African or African-American subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 255.2 fold 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 gnomAD may not be accurate due to the sequencing technology used being unable to distinguish between PMS2 and its many overlapping pseudogenes. c.2182A>G has been reported in the literature in individuals with a family history of cancer (Hu_2015, Paulo_2018, Martin-Morales_2018, Antonarakis_2019), however the technology used in these papers was NGS and not long-range PCR, therefore these occurrences may have come from a highly homologous pseudogene rather than PMS2. These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s), BRCA2, and SDHB have also been reported in our internal database, 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. Based on the evidence outlined above, the variant was classified as likely benign.
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.
Pathway Genomics RCV000172820 SCV000223786 uncertain significance Lynch syndrome I 2014-10-30 no assertion criteria provided 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

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