ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.1595G>A (p.Cys532Tyr)

gnomAD frequency: 0.00026  dbSNP: rs35963548
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122821 SCV000166078 likely benign Ataxia-telangiectasia syndrome 2021-12-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129230 SCV000183985 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-18 criteria provided, single submitter clinical testing The p.C532Y variant (also known as c.1595G>A), located in coding exon 9 of the ATM gene, results from a G to A substitution at nucleotide position 1595. The cysteine at codon 532 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant was reported in a mantle cell lymphoma in conjunction with the ATM p.N750K variant. This individual's tumor exhibited normal ATM protein expression (Camacho E et al. Blood. 2002 Jan;99:238-44). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000589072 SCV000209687 uncertain significance not provided 2022-05-13 criteria provided, single submitter clinical testing Observed in individuals with breast, prostate, colorectal, and other cancers, as well as in unaffected controls (Camacho 2002, Renwick 2006, Hirsch 2008, Tavtigian 2009, Lu 2015, Ballinger 2016, Nadeu 2016, Decker 2017, Tavera-Tapia 2017, Hauke 2018, Martin-Morales 2018, Paulo 2018, Pastorino 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20305132, 28779002, 29659569, 30256826, 16832357, 29522266, 11756177, 19781682, 17333338, 24728327, 27913932, 26689913, 22529920, 24356096, 27498913, 26837699, 30995915, 30303537, 31780696, 32325837, 33436325, 34646395)
Fulgent Genetics,Fulgent Genetics RCV000515290 SCV000611345 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 RCV000120116 SCV000694188 likely benign not specified 2021-02-08 criteria provided, single submitter clinical testing Variant summary: ATM c.1595G>A (p.Cys532Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 251486 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.00027 vs 0.001), allowing no conclusion about variant significance. c.1595G>A has been reported in the literature in individuals affected with various types of cancer (example, breast, mantle cell lymphoma, head and neck squamous cell carcinoma), in settings of multigene panel testing in families negative for BRCA1/2, and in unaffected controls (example, Camacho_2002, Bernstein_2010, Tavtigian_2009, Lu_2015, Tavera-Tapia_2017, Dutil_2019, Girard_2019, Gomes_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. 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 (likely benign, n=2; VUS, n=5). Based on the evidence outlined above, the variant retained its classification as likely benign.
PreventionGenetics,PreventionGenetics RCV000589072 SCV000805499 uncertain significance not provided 2017-12-06 criteria provided, single submitter clinical testing
Mendelics RCV000122821 SCV000838491 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000129230 SCV000910639 likely benign Hereditary cancer-predisposing syndrome 2016-04-25 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001798377 SCV002042637 uncertain significance Breast and/or ovarian cancer 2020-11-09 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000120116 SCV002070890 uncertain significance not specified 2021-12-20 criteria provided, single submitter clinical testing DNA sequence analysis of the ATM gene demonstrated a sequence change, c.1595G>A, in exon 10 that results in an amino acid change, p.Cys532Tyr. This sequence change has been described in the gnomAD database with a frequency of 0.082% in the Latino/Admixed American subpopulation (dbSNP rs35963548). The p.Cys532Tyr change affects a moderately conserved amino acid residue located in a domain of the ATM protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Cys532Tyr substitution. This sequence change has been previously described in individuals with different types of cancers, an individual with a history of aplastic anemia or idiopathic pulmonary fibrosis, as well as in healthy individuals (PMID: 29659569, 31780696, 30303537, 28779002, 7913932, 29514593, 30256826, 30995915, FLOSSIES database https://whi.color.com/variant/11-108121787-G-A). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Cys532Tyr change remains unknown at this time.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002243780 SCV002512208 uncertain significance Familial cancer of breast 2021-10-20 criteria provided, single submitter clinical testing ACMG classification criteria: PS4 supporting
Sema4,Sema4 RCV000129230 SCV002532749 likely benign Hereditary cancer-predisposing syndrome 2020-12-28 criteria provided, single submitter curation
Mayo Clinic Laboratories,Mayo Clinic RCV000589072 SCV002541169 uncertain significance not provided 2022-01-12 criteria provided, single submitter clinical testing
ITMI RCV000120116 SCV000084253 not provided not specified 2013-09-19 no assertion provided reference population
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355212 SCV001550031 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Cys532Tyr variant was identified in 1 of 13394 proband chromosomes (frequency: 0.00007) from individuals or families with breast cancer and in 5 of 7392 control chromosomes (frequency: 0.001) from healthy individuals (Bernstein_2010_20305132, Bodian_2014_24728327, Hirsch_2008_ 17333338, Renwick_2006_16832357, Tavtigian_2009_19781682). In a study of ATM alterations in mantle cell lymphoma, the variant was identified in the tumours and normal tissue of affected individuals; in addition, healthy blood donors were found to carry the variant at frequencies similar to those of tumor patients, the variant thereby considered a polymorphism found frequently in healthy populations (Camacho 2002 11756177). The variant was also identified in dbSNP (ID: rs35963548) as “With Uncertain significance allele”, ClinVar (classified with conflicting interpretations of pathogenicity: likely benign by Laboratory Corporation of America; uncertain significance by Invitae, Ambry Genetics, GeneDx, Fulgent Genetics; and classification not provided by ITMI), and Clinvitae (4x), and not in COGR, Cosmic, MutDB, and LOVD 3.0. The variant was identified in control databases in 66 of 276820 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 2 of 24016 chromosomes (freq: 0.00008), Other in 10 of 6456 chromosomes (freq: 0.002), Latino in 27 of 34412 chromosomes (freq: 0.0008), and European Non-Finnish in 27 of 126410 chromosomes (freq: 0.0002), but not in the Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The variant was identified by our laboratory in 1 individual with breast cancer, co-occurring with a pathogenic BRCA2 variant (c.2830A>T, p. p.Lys944X), increasing the likelihood the p.Cys532Tyr does not have clinical significance. The p.Cys532 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Tyr 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.
Molecular Oncology - Human Genetics Lab,University of Sao Paulo RCV001843478 SCV002103102 uncertain significance Hepatoblastoma no assertion criteria provided research

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