Description
Variant summary: PMS2 c.2012C>T (p.Thr671Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 168512 control chromosomes. The observed variant frequency is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05). However, this PMS2 locus is highly homologous to PMS2 pseudogene and the technology utilized for these datasets does not rule out pseudogene interference, therefore these data might not be reliable. c.2012C>T has been reported in the literature in individuals affected with breast cancer, colorectal cancer, ovarian cancer or pancreatic cancer (e.g. Tung 2015, Hu 2016, Yang 2016, Yurgelun 2017, Goidescu 2018, Rizzolo_2019, Tsaousis_2019, Duzkale_2021, Sahin_2022, Abdel-Razeq_2022, Dorling_2021, Delahunty_2022,) but has also been reported in individual(s) without a cancer diagnosis (e.g. Kraemer_2019). One of the reported colorectal cancer patients had a co-occurring pathogenic variant (KRAS c.34G>T, p.Gly12Cys) while the patient's tumor was determined to be MMR proficient and microsatellite stable (Yurgelun_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35402282, 35263119, 33471991, 34271781, 29785153, 35372080, 26483394, 31422574, 30613976, 35089076, 31159747, 25186627, 27449771, 28135145, 33120919, 30113427). ClinVar contains an entry for this variant (Variation ID: 127770). Based on the evidence outlined above, the variant was classified as uncertain significance.
# | Sample | Method | Observation |
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Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
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1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |