ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.2289T>A (p.Phe763Leu) (rs34231402)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000211979 SCV000149061 likely benign not specified 2017-11-20 criteria provided, single submitter clinical testing 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.
Invitae RCV000122834 SCV000166092 benign Ataxia-telangiectasia syndrome 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115152 SCV000172935 likely benign Hereditary cancer-predisposing syndrome 2018-08-24 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign);No disease association in small case-control study
Fulgent Genetics,Fulgent Genetics RCV000515303 SCV000611351 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000211979 SCV000694216 likely benign not specified 2019-01-14 criteria provided, single submitter clinical testing Variant summary: ATM c.2289T>A (p.Phe763Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00068 in 278714 control chromosomes, predominantly at a frequency of 0.0018 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin.The variant has been identified in numerous HBOC patients and control cohorts reported in the literature, without evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with other pathogenic variant(s) have been reported (SMAD4 c.1194G>A, p.W398X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (5 benign/likely benign, 2 VUS). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics,PreventionGenetics RCV000588896 SCV000805515 likely benign not provided 2017-11-29 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115152 SCV000821837 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000122834 SCV000838502 likely benign Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115152 SCV000902588 benign Hereditary cancer-predisposing syndrome 2015-11-10 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000122834 SCV001262547 uncertain significance Ataxia-telangiectasia syndrome 2017-04-27 criteria provided, single submitter clinical testing 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000211979 SCV001469347 benign not specified 2020-07-02 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000211979 SCV001474788 benign not specified 2020-07-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355251 SCV001550080 likely benign Familial ovarian cancer no assertion criteria provided clinical testing The ATM p.Phe763Leu variant was identified in 10 of 8114 proband chromosomes (frequency: 0.0012) from individuals or families with breast cancer, Hodgkin’s Disease and individuals testing for Lynch Syndrome; the variant was present in 7 of 5394 control chromosomes (frequency: 0.012) from healthy individuals (Sommer_2002_11996792, Offit_2002_12473594, Hirsch_2008_17333338, Paglia_2010_19404735, Tavtigian-2009_19781682, Yurgelun_2015_22529920). The variant was also identified in dbSNP (ID: rs34231402) as “With Uncertain significance allele”, ClinVar (2x as uncertain significance by GeneDx and Flugent Genetics, 1x as likely benign by Ambry Genetics, 1x as benign by Invitae), Clinvitae (3x as likely benign and uncertain significance) databases. The variant was not identified in Cosmic, MutDB and LOVD 3.0, databases. The variant was identified in control databases in 186 of 277044 chromosomes (1 homozygous) at a frequency of 0.0007 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 42 of 24034 chromosomes (freq: 0.0012), Other in 14 of 6462 chromosomes (freq: 0.002), Latino in 63 of 34418 chromosomes (freq: 0.002), European Non-Finnish in 54 of 126666 chromosomes (freq: 0.0004), Ashkenazi Jewish in 13 of 10152 chromosomes (freq: 0.0013), while the variant was not observed in the East Asian, European Finnish, and South Asian populations. The p.Phe763Leu residue is conserved in 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 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.

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