ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1464G>T (p.Trp488Cys) (rs377597949)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131552 SCV000186553 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-25 criteria provided, single submitter clinical testing The p.W488C variant (also known as c.1464G>T), located in coding exon 9 of the ATM gene, results from a G to T substitution at nucleotide position 1464. The tryptophan at codon 488 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a proband with hereditary breast and/or ovarian cancer (Castera L et al. Eur. J. Hum. Genet. 2014 Nov;22:1305-13) and also in an individual who underwent multigene panel testing for hereditary cancer (Yorczyk A​ et al. Clin. Genet. 2015 Sep;88:278-82). Further, this alteration has been reported with a carrier frequency of 0.00028 in 7051 unselected breast cancer patients and 0.00 in 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083), and in one individual from a cohort of Spanish hereditary breast and ovarian cancer families (Tavera-Tapia A et al. Breast Cancer Res. Treat., 2017 02;161:597-604). In one case-control study, this alteration was detected in 1/2399 healthy controls, but not in 4112 breast cancer cases (Tavtigian SV Am. J. Hum. Genet. 2009 Oct;85:427-46). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000235099 SCV000209776 uncertain significance not provided 2021-07-14 criteria provided, single submitter clinical testing Observed in individuals with a personal or family history including breast and other cancers (Castera 2014, Yorczyk 2015, Tavera-Tapia 2017, Decker 2017, Renault 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 33436325, 27535533, 3030537, 29665859, 28779002, 26787654, 27913932, 25318351, 19781682, 24549055, 30303537)
Invitae RCV000168391 SCV000219084 likely benign Ataxia-telangiectasia syndrome 2020-12-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515383 SCV000611343 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131552 SCV000902980 likely benign Hereditary cancer-predisposing syndrome 2016-04-27 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001199851 SCV001370583 uncertain significance not specified 2020-05-26 criteria provided, single submitter clinical testing Variant summary: ATM c.1464G>T (p.Trp488Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251336 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1464G>T has been reported in the literature in sequencing studies of individuals affected with Breast and other types of cancer (example, Castera_2014, Yorczyk_2015, Young_2016, Tavera-Tapia_2017, Renault_2018, Momozawa_2018, Girard_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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 (VUS, n=3; likely benign, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357286 SCV001552707 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Trp488Cys variant was identified in 2 of 6688 proband chromosomes (frequency: 0.0003) from individuals or families with breast and ovarian cancer and was present in 1 of 4490 control chromosomes (frequency: 0.0002) from healthy individuals (Castera 2014, Tavtigian 2009, Yorczyk 2015). The variant was also identified in dbSNP (ID: rs377597949) as “With Uncertain significance allele”, and in ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Invitae and Fulgent Genetics). The variant was not identified in the COGR, Cosmic, MutDB, or LOVD 3.0 databases. The variant was identified in control databases in 5 of 277070 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 2 of 34408 chromosomes (freq: 0.0001), and European in 3 of 126594 chromosomes (freq: 0.00002); it was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Trp488 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the 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 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000235099 SCV001743528 uncertain significance not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000235099 SCV001807400 uncertain significance not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000235099 SCV001957583 uncertain significance not provided no assertion criteria provided clinical testing

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