Description
Variant summary: ATM c.1986T>C alters a 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 0.00048 in 277242 control chromosomes, predominantly at a frequency of 0.0011 within the Ashkenazi Jewish subpopulation and at a frequency of 0.00083 in the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish and Non-Finnish European control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism. c.1986T>C has been reported in the literature in individuals affected with cancer, including breast cancer, non-Hodgkin lymphoma and chronic lymphocytic leukemia (Skowronska_2012, Bernstein_2010, Sipahimalani_2007, Vorechovsky_1996). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with other pathogenic variants have been reported in our internal database (PALB2 c.761C>G, p.Ser254X; BRCA1 c.68_69delAG, p.E23fs*17), providing supporting evidence for a benign role. Additionally, the variant was detected in heterozygous state in 12 control individuals in the FLOSSIES database (individuals aged over 70 who never had cancer), providing further supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
