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

gnomAD frequency: 0.00026  dbSNP: rs35963548

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122821	SCV000166078	likely benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129230	SCV000183985	likely benign	Hereditary cancer-predisposing syndrome	2021-05-06	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
GeneDx	RCV000589072	SCV000209687	uncertain significance	not provided	2024-07-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast, prostate, colorectal, and other cancers, as well as in unaffected controls (PMID: 11756177, 16832357, 17333338, 19781682, 26689913, 27498913, 26837699, 28779002, 27913932, 29522266, 30256826, 29659569, 32325837, 33359728, 35495172, 35534704, 35264596, 34326862, 35980532); 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, 34262154, 33128190, 35495172, 33359728, 35534704, 35264596, 34326862, 35980532)
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	2024-01-22	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 0.00018 in 1615282 control chromosomes, predominantly at a frequency of 0.00088 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (0.00018 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. The following publications have been ascertained in the context of this evaluation (PMID: 35980532, 20305132, 24728327, 11756177, 34262154, 31780696, 30303537, 33128190, 17333338, 26689913, 26837699, 37436117, 16832357, 27913932, 19781682). ClinVar contains an entry for this variant (Variation ID: 133603). Based on the evidence outlined above, the variant retained its classification as likely benign.
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	likely benign	Breast and/or ovarian cancer	2023-04-05	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
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589072	SCV004219994	likely benign	not provided	2023-06-02	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002243780	SCV005083849	likely benign	Familial cancer of breast	2024-04-30	criteria provided, single submitter	clinical testing	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].
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120116	SCV005090014	likely benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
ITMI	RCV000120116	SCV000084253	not provided	not specified	2013-09-19	no assertion provided	reference population
PreventionGenetics, part of Exact Sciences	RCV004739411	SCV000805499	uncertain significance	ATM-related disorder	2024-05-02	no assertion criteria provided	clinical testing	The ATM c.1595G>A variant is predicted to result in the amino acid substitution p.Cys532Tyr. This variant has been reported in individuals with mantle cell lymphoma, chronic lymphocytic leukemia, prostate cancer, cutaneous melanoma, telomere shortening, or a personal and/or family history of breast and/or ovarian cancer (Camacho et al. 2002. PubMed ID: 11756177; Table S8, Nadeu et al. 2016. PubMed ID: 26837699; Table S1, Tavera-Tapia et al. 2017. PubMed ID: 27913932; Table S3, Girard et al. 2018. PubMed ID: 30303537; Paulo et al. 2018. PubMed ID: 29659569; Arias-Salgado et al. 2019. PubMed ID: 30995915; Dutil et al. 2019. PubMed ID: 31780696; Pastorino et al. 2020. PubMed ID: 32325837; Table S4, Karlsson et al. 2021. PubMed ID: 33436325). However, it has also been reported in unaffected control cohorts (Table S2, Tavtigian et al. 2009. PubMed ID: 19781682; Table S3, Girard et al. 2018. PubMed ID: 30303537; Dorling et al. 2021. PubMed ID: 33471991). This variant is reported in 0.082% of alleles in individuals of Latino descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/133603/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
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