ClinVar Genomic variation as it relates to human health

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 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.

Variant summary: The ATM variant, c.1810C>T (p.Pro604Ser) causes a missense change involving a conserved nucleotide with 2/4 in silico programs (SNPs&GO not captured here due to low reliability index) predict a "benign" outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 345/111640 (1/323 including 5 homozygotes), which significantly exceeds the estimated maximum expected allele frequency for a pathogenic ATM variant of 1/2000 for Breast Cancer. Therefore, suggesting the variant is a common polymorphism. The variant of interest has been reported in multiple affected individuals via publications with varying phenotypes (BrC, Lynch syndrome, B-CLL, PrC, lymphoma, Hodgkin's disease), including one individual dx with A-T that harbored this variant and another ATM variant, c.6482G>C (p.Arg2161Pro - not yet scored) and was indicated to have absent ATM protein. Two internal LCA samples (adult patients with unknown phenotypes) carried c.1810C>T variant with another pathogenic variants: 1 with a BRIP1 variant, c.440dupA (Tyr147X - classified likely pathogenic) and 1 with an ATM variant, c.1027_1030delGAAA (p.Glu343fsX2 - classified pathogenic). In addition, multiple reputable clinical laboratories cite the variant with a classification of "likely benign/benign." Therefore, taking all available information into consideration for the phenotype of Breast Cancer, the variant of interest is classified as Benign.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2.

The c.1810C>T (p.Pro604Ser) missense variant has an allele frequency of 0.32%, (895/281,544 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.65%, (153/23,556 alleles) in the African subpopulation (BA1; http://gnomad.broadinstitute.org). Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BA1 (+BS2_Supporting) (PMID: 33280026).

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, BS2

The ATM p.Pro604Ser variant was identified in 12 of 2910 proband chromosomes (frequency: 0.0041) from individuals or families with breast cancer, ovarian cancer, Ataxia Telangiectasia and several types of lymphomas and was present in 8 of 900 control chromosomes (frequency: 0.009) from healthy individuals (Broeks 2008, Dork 2001, Fang 2003, Gronbaek 2002, Verhagen 2011). The variant was also identified in dbSBP (ID: rs2227922) as “With Likely benign allele”, ClinVar (as likely benign by EGL Diagnostics, Genetic Services Laboratory Chicago, and GeneDx, and as benign by Invitae, Ambry Genetics and Color Genomics), Clinvitae (4x as benign and likely benign), and Cosmic (8x) databases. The variant was not identified in MutDB, LOVD 3.0, ATM-LOVD, databases. The variant was identified in control databases in 887 of 275954 chromosomes at a frequency of 0.003214 in the following populations: Ashkenazi Jewish in 332 (10 homozygous) of 10120 chromosomes (freq. 0.0328), Other in 49 (3 homozygous) of 6424 chromosomes (freq. 0.0076), African in 161 of 23966 chromosomes (freq. 0.0067), Latino in 135 (1 homozygous) of 34286 chromosomes (freq. 0.0039), European (Non-Finnish) in 191 of 126004 chromosomes (freq. 0.0015), South Asian in 16 (1 homozygous) of 30606 chromosomes (freq. 0.0005), and European (Finnish) in 3 of 25730 chromosomes (freq. 0.0001), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). A study of Hodgkin’s lymphoma patients postulated that the p.Pro604Ser variant creates a new glycosylation site which might interfere with ATM function and protein–protein interaction (Offit 2002). The p.Pro604Ser variant was found to co-occur with p.Phe1463Cys in 2 individuals with Non-Hodgkin’s lymphoma (Liberzon 2004). The p.Pro604 residue is conserved in in mammals but not in more distantly related organisms, and the variant amino acid Serine (Ser) is present in the African tree frog, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the 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 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.

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Variant interpreted as Likely benign and reported on 12-22-2014 by GeneDx. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.