ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.1595G>A (p.Cys532Tyr) (rs35963548)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122821 SCV000166078 likely benign Ataxia-telangiectasia syndrome 2020-12-01 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 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.
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 Health, Inc RCV000129230 SCV000910639 likely benign Hereditary cancer-predisposing syndrome 2016-04-25 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.

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