ClinVar Genomic variation as it relates to human health

This variant is interpreted as a Benign, for Ataxia-telangiectasia, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BS3 => Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing (PMID:19431188).

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.

Variant summary: The ATM c.5071A>C (p.Ser1691Arg) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 493/276958 control chromosomes (3 homozygotes) at a frequency of 0.001780, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005), suggesting this variant is likely a benign polymorphism. The variant has been reported in multiple breast cancer cases and cancer families, and in one ataxia-telangiectasia patient. None of the publications provide strong evidence for causality, lacking co-occurrence and co-segregation data, and often not providing the BRCA status of affected individuals. Multiple reputable clinical labs have classified this variant as likely benign/benign, without evidence to independently evaluate. Taken together, based on the prevalence in general population and by applying ACMG rules, the variant was classified as benign.

This variant is associated with the following publications: (PMID: 24728327, 11606401, 26979391, 28652578, 22420423, 22250480, 25742471, 14754616, 19431188, 9463314, 25980754, 26787654, 11505391, 27153395, 28202063, 28196074, 26933808, 28695297, 25133958, 28767289)

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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

The c.5071A>T (p.Ser1691Arg) missense variant has an allele frequency of 0.18%, (476/268,092 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.30%, (354/117,946 alleles) in the European (non-Finnish) subpopulation (BS1; http://gnomad.broadinstitute.org). This variant has also been observed in homozygosis in 3 individuals of the gnomAD v2.1.1 non-neuro dataset (BS2_Supporting). Functional studies with the variant protein modelled in an ATM-null lymphoblastoid cell line and proper controls showed that: 1) the level of ATM protein was comparable to that of the positive control; 2) the ability of the modeled protein to phosphorylate Smc1, Nbs1, Chk2, and p53 following exposure of the cells to ionizing radiation and to autophosphorylate serine 1981 was also no different from the positive control; 3)The variant protein formed foci that colocalized with yH2AX following exposure to ionizing radiation (BS3; PMID:19431188). Therefore, this variant meets criteria to be classified as benign. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BS1 + BS2_Supporting + BS3 (PMID: 33280026).

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].

ATM: BP4, BS1

The ATM p.Ser1691Arg variant was identified in 20 of 5886 proband chromosomes (frequency: 0.003) from American, Dutch and Lebanese individuals or families with breast cancer (high risk or familial or nonfamilial) or a history of Lynch syndrome associated cancer and/or polyps or individuals with unspecified cancer undergoing radiotherapy, and was identified in 4 of 3578 control chromosomes from healthy individuals (frequency: 0.001) (Petereit_2013_24416720, Broeks_2008_17393301, Jalkh_2017_28202063, Teraoka_2001_11505391, Bodian_2014_24728327, Yurgelun_2015_25980754 , Stredrick_2006_16652348). Functional studies using an expression construct to model ATM missense variants showed the variant’s level of ATM protein expression and kinase activity was comparable to wildtype (Barone_2009_19431188). The variant was identified in dbSNP (ID: rs1800059) “With other allele”, ClinVar (classified benign by Invitae, Ambry Genetics, EGL Genetic Diagnostics (Eurofins Clinical Diagnostics), likely benign by GeneDx, ARUP and classification not provided by ITMI), Clinvitae (3x), Cosmic (seen 2x in a malignant melanoma, 1x in a haematopoietic neoplasm and 3x in a carcinoma of the large intestine), LOVD 3.0 (1x), and was not identified MutDB. The variant was also identified in control databases in 493 (3 homozygous) of 276958 chromosomes at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 13 of 24030 chromosomes (freq: 0.0005), “Other” in 12 of 6458 chromosomes (freq: 0.002), Latino in 24 of 34416 chromosomes (freq: 0.0007), European Non-Finnish in 372 (2 homozygous) of 126472 chromosomes (freq: 0.003), and European Finnish in 72 (1 homozygous) of 25790 chromosomes (freq: 0.003); it was not observed in the Ashkenazi Jewish, East Asian and South Asian populations. The p.Ser1691 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 the variant Arg impacts 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 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.