ClinVar Genomic variation as it relates to human health

The ATM c.2614C>T (p.Pro872Ser) variant has a GnomAD FAF 4.6% (AFR) exceeding ATM BA1 threshold of .5% (BA1). This variant has been observed in a homozygous or compound heterozygous state (presumed and/or confirmed) in multiple individuals without Ataxia-Telangiectasia (BP2_Strong, Clinical Diagnostic Laboratories). This variant is predicted tolerated by multiple protein in silico tools (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel.

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 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

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.

This variant is considered 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]. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.

ATM: BP4, BS1, BS2

The ATM p.Pro872Ser variant was identified in 10 of 1192 proband chromosomes (frequency: 0.008) from individuals or families with breast cancer, multiple myeloma and from breast cancer tumors and was not identified in 200 control chromosomes from healthy individuals (Austen 2008, Rodriguez 2002, Bretsky 2003). The variant was also identified in the following databases: dbSNP (ID: rs3218673) as “With other allele”, in ClinVar (classified as 5x benign and 1x likely benign), Clinvitae (classified as 5x benign and 1x conflicting interpretations of pathogenicity), and Cosmic (1x as neutral). The variant was not identified in the MutDB, LOVD 3.0, or ATM-LOVD databases. The variant was identified in control databases in 1212 of 277156 (32 homozygous) chromosomes at a frequency of 0.004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: African in 1102 of 24020 chromosomes (freq: 0.046). The p.Pro872Ser residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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.