ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1242C>T (p.Asp414=) (rs142839559)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166893 SCV000217710 likely benign Hereditary cancer-predisposing syndrome 2014-12-08 criteria provided, single submitter clinical testing
Invitae RCV001079179 SCV000285056 benign Hereditary nonpolyposis colon cancer 2019-12-31 criteria provided, single submitter clinical testing
Color RCV000166893 SCV000686110 likely benign Hereditary cancer-predisposing syndrome 2016-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589485 SCV000697288 likely benign not specified 2019-01-25 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1242C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00013 in 277098 control chromosomes, predominantly at a frequency of 0.0011 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 10 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 origin. However, this observation needs to be cautiously considered due to the possibility of the PMS2 pseudogene being captured. To our knowledge, no occurrence of c.1242C>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variants have been reported in our internal database (example CHEK2 c.1100delC, p.Thr367fsX15), providing supporting evidence for a benign role. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign (1x) and once as benign. Based on the evidence outlined above, the variant was classified as likely benign.

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