ClinVar Genomic variation as it relates to human health

Variant summary: Variant affects a non-conserved nucleotide and results in a replacement of a large size and aromatic Phenylalanine (F) with a medium size and hydrophobic Leucine (L). 4/4 in silico tools predict the variant to be neutral. It was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.098% which does not exceed the maximal expected allele frequency of a disease causing AT allele (0.4%). The variant was reported in CLL, ALL and breast cancer patients, however without information about family history and co-segregation, therefore these reports do not provide strong evidence for a casual impact of the variant. It was reported as a germline alteration in a patient with T-ALL associated with a t(11:14) translocation by cytogenetic analysis with no evidence of an allelic loss in tumor DNA. One publication suggest the variant to confer a risk for CLL (OR:11.23) based on a case control study, however, the significance of this finding is uncertain due to the OR being calculated based on only one affected patient (Rudd_Blood_2006). In other studies, reporting an OR for association with sporadic T-ALL, the 95% CI's overlapped 1.0, and had very small sample sizes, thereby providing little to no confidence in the assertion of the assertion. On study reported the variant to result in normal ATM protein levels, normal kinase activity, and corrected radiosensitivity when expressed in A-T cells indicating neutrality. At least three publications (Mitui_Hum Mut_2009, Magliozzi_DiseaseMarkers_2006, Maxwell_AJHG_2016) and several clinical diagnostic laboratories classify this variant as Benign/Likely Benign. Considering all evidence, the variant was classified as Likely Benign until more information becomes available.

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

ATM: BP4

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].

The ATM p.Phe582Leu variant was identified in 3 of 3466 proband chromosomes (frequency: 0.0009) from individuals or families tested for Lynch Syndrome and with breast cancer (Johnson_2007, Yurgelun_2015). The variant was also identified in the following databases: dbSNP (ID: rs2235006) as “With Likely benign allele”, ClinVar (reported 7x, as benign by Invitae, Ambry Genetics, as likely benign by EGL Genetics, PreventionGenetics, University of Chicago, GeneDx, and ITMI without any pathogenicity predictions), Clinvitae (4x, as benign and likely benign by ClinVar, Invitae, EmvClass) and LOVD 3.0 (2x as "Probably does not affect function" prediction). The variant was not identified in the Cosmic or MutDB databases. The variant was identified in control databases in 257 of 276854 chromosomes (1 homozygous) at a frequency of 0.0009 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 24020 chromosomes (freq: 0.000042), Other in 11 of 6454 chromosomes (freq: 0.002), Latino in 46 of 34400 chromosomes (freq: 0.0013), European Non-Finnish in 132 of 126444 chromosomes (freq: 0.001), Ashkenazi Jewish in 11 of 10148 chromosomes (freq: 0.001), and South Asian in 56 of 30774 chromosomes (freq: 0.002); it was not in the East Asian, or European Finnish populations. Constructs of the ATM c.1744T>C variant were utilized as a control in an A-T cells transfection study (Mitui_2009). The aim of the experiment was to identify site-directed mutagenesis for distinguishing polymorphisms from mutations in the ATM gene. The study demonstrated that transfecting A-T cells (AT7LA) with constructs of ATM, c.1744T>C variant yielded normal ATM protein levels, normal kinase activity, and corrected radiosensitivity, supporting classification of this variant as likely benign. The p.Phe582 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.