ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1595G>A (p.Cys532Tyr) (rs35963548)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129230 SCV000183985 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000129230 SCV000910639 likely benign Hereditary cancer-predisposing syndrome 2016-04-25 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515290 SCV000611345 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000589072 SCV000209687 uncertain significance not provided 2018-10-08 criteria provided, single submitter clinical testing This variant is denoted ATM c.1595G>A at the cDNA level, p.Cys532Tyr (C532Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGC>TAC). This variant was observed in individuals with a personal and/or family history of breast cancer as well as in individuals with prostate cancer, colorectal cancer, mantle cell lymphoma, squamous cell carcinoma, osteosarcoma, and chronic lymphocytic leukemia (Camacho 2002, Lu 2015, Ballinger 2016, Nadeu 2016, Decker 2017, Tavera-Tapia 2017, Hauke 2018, Martin-Morales 2018, Paulo 2018). However, this variant has also been observed in unaffected controls (Camacho 2002, Renwick 2006, Hirsch 2008, Tavtigian 2009, Decker 2017, Paulo 2018). ATM Cys532Tyr was observed at an allele frequency of 0.08% (27/34,412) in individuals of Latino ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Cys532Tyr is pathogenic or benign. We consider it to be a variant of uncertain significance.
ITMI RCV000120116 SCV000084253 not provided not specified 2013-09-19 no assertion provided reference population
Integrated Genetics/Laboratory Corporation of America RCV000589072 SCV000694188 likely benign not provided 2017-06-05 criteria provided, single submitter clinical testing Variant summary: The ATM c.1595G>A (p.Cys532Tyr) variant involves the alteration of a conserved nucleotide and 4/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a damaging outcome for this variant. This variant was found in 28/121924 control chromosomes, predominantly observed in the Latino subpopulation at a frequency of 0.0013848 (16/11554). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0005001), suggesting this is likely a benign polymorphism found primarily in the populations of Latino origin. The variant was found in affected individuals presented with lymphoma, head and neck squamous carcinoma, and breast cancer without strong evidence for pathogenicity. In addition, the variant of interest was found to co-occur with a known pathogenic mutation c.68_69delAG in BRCA1 in an individual referred for genetic testing in our facility, strongly supporting for benign outcome. Even though multiple clinical diagnostic laboratories/reputable databases classified this variant as "uncertain significance," although, a publication, Camacho_2002, refers to the variant as a "polymorphism." Therefore, due to the frequency in controls and co-occurrence with a pathogenic BRCA1 variant, the variant of interest has been classified as "likely benign."
Invitae RCV000122821 SCV000166078 uncertain significance Ataxia-telangiectasia syndrome 2018-12-22 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 532 of the ATM protein (p.Cys532Tyr). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is present in population databases (rs35963548, ExAC 0.1%). This variant has been reported in individuals affected with breast cancer, prostate cancer, mantle cell lymphoma and chronic lymphocytic leukemia (PMID: 20305132, 29659569, 11756177, 26837699), as well as unaffected individuals (PMID: 11756177, 17333338). In a large meta-analysis studying the association of ATM missense variants with increased risk of breast cancer, this c.1595G>A substitution showed no evidence for increased cancer risk (0/2,531 cases vs. 2/2,245 controls) (PMID: 19781682). ClinVar contains an entry for this variant (Variation ID: 133603). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mendelics RCV000122821 SCV000838491 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
PreventionGenetics RCV000589072 SCV000805499 uncertain significance not provided 2017-12-06 criteria provided, single submitter clinical testing

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