ATRIP was first reported concerning autosomal dominant inheritance and breast cancer susceptibility in 2023 (Cybulski C, et al., PMID: 36977412). Breast cancer (referring to mammary carcinoma) is histopathological and almost certainly etiologically and genetically heterogeneous. Familial occurrence has indicated important genetic factors (OMIM 114480). Per the criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. One variant (ATRIP:c.1152_1155del) reported in breast cancer patients in one publication (PMID: 36977412) is included in this curation. More evidence is available in the literature (Wilcox N, et al., PMID: 37592023), reported associations between protein-truncating variants in ATRIP and breast cancer (P < 1 × 10−4.). The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by experimental evidence from in vitro functional assays (PMID: 36977412). Immunohistochemistry and functional studies showed the ATRIP c.1152_1155del variant allele is weakly expressed compared to the wild-type allele, and truncated ATRIP fails to perform its normal function to prevent replicative stress. In summary, limited evidence supports the relationship between ATRIP and autosomal dominant inheritance Breast cancer susceptibility. This relationship has been demonstrated in patients with monoallelic mutations in ATRIP (PMIDs: 36977412, 37592023). The ClinGen Hereditary Cancer GCEP approved this classification on the meeting date of May 24, 2024 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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