Description
The ATM p.Ser333Phe variant was identified in 9 (1 homozygous) of 2296 proband chromosomes (frequency: 0.004) from Finnish and American individuals or families with non-BRCA1/2 breast cancer, breast cancer, early onset and familial CRC, and individuals undergoing radiation therapy, and was identified in 37 of8118 chromosomes from healthy (race matched controls) (Petereit 2013, Tommiska 2006, Teraoka 2001, Tanskanen 2015). Segregation studies in 1 family were negative, as the proband’s 3 affected sisters were non-carriers (Tommiska 2006). The variant was also identified in dbSNP (ID: rs28904919) “With Likely benign allele”, ClinVar (classified benign by Invitae, likely benign by GeneDx, Ambry Genetics and ARUP, and classification not provided by ITMI), Clinvitae (3x), Cosmic (2x in a hemangioblastoma and adnexal tumour) and not in MutDB and LOVD 3.0. The variant was identified in control databases in 439 of 276964 chromosomes (1 homozygous) at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 8 of 24024 chromosomes (freq: 0.0003), Other in 9 of 6462 chromosomes (freq: 0.001), Latino in 125 (1 homozygous) of 34380 chromosomes (freq: 0.004), European Non-Finnish in 209 of 126534 chromosomes (freq: 0.002), European Finnish in 88 of 25784 chromosomes (freq: 0.003), while not observed in the Ashkenazi Jewish, East Asian, and South Asian populations. The p.Ser333 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Phe variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | unknown | yes | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
