Submissions for variant NM_000051.4(ATM):c.1464G>T (p.Trp488Cys)

gnomAD frequency: 0.00003  dbSNP: rs377597949

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131552	SCV000186553	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-30	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	2024-05-05	criteria provided, single submitter	clinical testing	Observed in individuals with a personal or family history including breast and other cancers (PMID: 24549055, 25318351, 27913932, 28779002, 30287823, 29665859, 33436325, 34326862); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25318351, 27913932, Carpenter2024[computational], 30303537, 24549055, 19781682, 26787654, 28779002, 29665859, 3030537, 30287823, 33436325, 33471991, 34326862, 36243179)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168391	SCV000219084	likely benign	Ataxia-telangiectasia syndrome	2024-01-06	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 Diagnostics, LLC DBA Color Health	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.
Genetic Services Laboratory, University of Chicago	RCV001199851	SCV002069601	uncertain significance	not specified	2019-08-26	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131552	SCV002530409	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-01	criteria provided, single submitter	curation
Baylor Genetics	RCV003462015	SCV004207100	uncertain significance	Familial cancer of breast	2024-01-15	criteria provided, single submitter	clinical testing
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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000235099	SCV001957583	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004551263	SCV004790588	uncertain significance	ATM-related disorder	2024-02-08	no assertion criteria provided	clinical testing	The ATM c.1464G>T variant is predicted to result in the amino acid substitution p.Trp488Cys. This variant has been reported in individuals with breast and/or ovarian cancer (see, for example, Table S1, Castéra et al 2014. PubMed ID: 24549055; Supplementary Table S3, Girard et al 2018. PubMed ID: 30303537; Supplementary Table 1, Tavera-Tapia et al. 2017. PubMed ID: 27913932) as well as in individuals with prostate cancer (Supplementary Table 4, Karlsson et al 2021. PubMed ID: 33436325). It has also been reported in a control individual (Tavtigian et al. 2009. PubMed ID: 19781682). This variant is reported in 0.0056% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as uncertain by majority of the submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142433/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.