ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.320G>A (p.Cys107Tyr) (rs142358238)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000589242 SCV000149082 uncertain significance not provided 2017-12-15 criteria provided, single submitter clinical testing This variant is denoted ATM c.320G>A at the cDNA level, p.Cys107Tyr (C107Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGT>TAT). This variant has been reported in the compound heterozygous state with a nonsense variant in one individual with Ataxia-telangiectasia (A-T), whose diagnosis was confirmed by clinical observation and radiation sensitivity testing (Bernstein 2003). This variant was also observed in at least two individuals undergoing hereditary cancer testing (Yorczyk 2014, Yurgelun 2015), and in at least one individual with acute myeloid leukemia (Lu 2015). Hirsch et al. (2008) did not identify ATM Cys107Tyr in a series of 31 African-American individuals with breast cancer, but did observe it in 1/95 age- and population-matched controls, and Decker et al. (2017) observed this variant in 1/13,087 breast cancer cases and 2/5,488 controls from the United Kingdom. This variant was also observed in a multi-ethnic breast cancer case/control study in which no statistically significant association with breast cancer was identified after correcting for multiple comparisons (Haiman 2013). ATM Cys107Tyr was observed at an allele frequency of 0.21% in individuals of African 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 Cys107Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115173 SCV000186495 likely benign Hereditary cancer-predisposing syndrome 2019-02-11 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Other data supporting benign classification;Subpopulation frequency in support of benign classification
Invitae RCV000198992 SCV000254081 likely benign Ataxia-telangiectasia syndrome 2020-11-26 criteria provided, single submitter clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000115173 SCV000576456 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-14 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515352 SCV000611357 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 RCV001260261 SCV000694251 likely benign not specified 2020-09-25 criteria provided, single submitter clinical testing Variant summary: ATM c.320G>A (p.Cys107Tyr) results in a non-conservative amino acid change located in the Telomere-length maintenance and DNA damage repair domain (IPR021668) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 250912 control chromosomes, predominantly at a frequency of 0.0021 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2.1 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 African or African-American origin. c.320G>A has been reported in the literature in sequencing studies of individuals with varied indications such as, an individual with Ataxia Telangiectasia (Bernstein_2003), as not associated with risk of breast cancer in an array GWAS study of a multiethnic population (Haiman_2013), an unaffected control of African American ancestry (Hirsch_2008), a patient undergoing multigene panel testing for cancer (Yorczyk_2015), a patient with a clinical indication of Lynch syndrome associated cancer and/or polyps undergoing multigene panel testing (Yurgelun_2015), and a patient with AML in the TGCA cohort (Lu_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer or Ataxia Telangiectasia. Additionally, the variant was found to occur in eleven women who are older than 70 years of age and cancer free as reported in the FLOSSIES database. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine 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=3). Some submitters have cited overlapping evidence utilized in the context of this evaluation. Based on the absence of any concrete evidence supporting an actionable outcome in over six years of evaluations performed at our laboratory spanning the evidences outlined above, the variant was re-classified as likely benign.
Counsyl RCV000198992 SCV000792422 uncertain significance Ataxia-telangiectasia syndrome 2017-06-23 criteria provided, single submitter clinical testing
Mendelics RCV000198992 SCV000838468 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000589242 SCV000861414 uncertain significance not provided 2018-06-05 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115173 SCV000910674 likely benign Hereditary cancer-predisposing syndrome 2015-10-29 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357199 SCV001552587 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Cys107Tyr variant was identified in 4 of 36,874 proband chromosomes (frequency: 0.0001) from individuals or families with ataxia tenlangiectasia, acute myeloid leukemia, Lynch Syndrome or breast cancer and was present in 3 of 11,166 control chromosomes (frequency: 0.0003) from healthy individuals (Bernstein 2003, Lu 2015, Yurgelun 2015, Hirsch 2008, Decker 2017). The variant was identified in dbSNP (rs142358238) as “with other allele” and ClinVar (classified as uncertain significance by Invitae, GeneDx, Counsyl and 5 other submitters; and as likely benign by Ambry Genetics and Color). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 60 of 281,758 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 53 of 24,862 chromosomes (freq: 0.002), Latino in 6 of 35,344 chromosomes (freq: 0.0002), and South Asian in 1 of 30,544 chromosomes (freq: 0.00003), while it was not observed in the Ashkenazi Jewish, East Asian, Finnish, European or Other populations. This variant was identified in the compound heterozygous state in an individual with ataxia telangiectasia with a co-occurring, pathogenic ATM variant (c.7327C>T, p.Arg2443*; Bernstein 2003). The p.Cys107 residue is conserved in mammals but not in more distantly related organisms, although four out of five 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) 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. This variant is classified as a variant of uncertain significance.

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