ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.4060C>A (p.Pro1354Thr) (rs145119475)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656759 SCV000149093 uncertain significance not provided 2018-10-30 criteria provided, single submitter clinical testing This variant is denoted ATM c.4060C>A at the cDNA level, p.Pro1354Thr (P1354T) at the protein level, and results in the change of a Proline to a Threonine (CCA>ACA). This variant has been observed in several individuals with breast cancer, but was also identified in healthy controls (Tavitigan 2009, Decker 2017, Hauke 2018). This variant has also been reported in an individual with kidney cancer and an individual with lung cancer (Lu 2015). ATM Pro1354Thr was observed at an allele frequency of 0.036% (45/124,128) in individuals of European ancestry in large population cohorts (Lek 2016). ATM Pro1354Thr is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Pro1354Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115184 SCV000185799 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-11 criteria provided, single submitter clinical testing The p.P1354T variant (also known as c.4060C>A), located in coding exon 26 of the ATM gene, results from a C to A substitution at nucleotide position 4060. The proline at codon 1354 is replaced by threonine, an amino acid with highly similar properties. This alteration has been detected in 1/4112 breast cancer patients and 1/2399 healthy control individuals across numerous studies (Tavtigian SV et al. 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.
Invitae RCV000168271 SCV000218943 benign Ataxia-telangiectasia syndrome 2020-11-30 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000193232 SCV000246617 uncertain significance not specified 2015-01-21 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000656759 SCV000805552 uncertain significance not provided 2018-01-08 criteria provided, single submitter clinical testing
Mendelics RCV000168271 SCV000838531 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115184 SCV000902664 likely benign Hereditary cancer-predisposing syndrome 2015-01-16 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000193232 SCV000918509 likely benign not specified 2020-11-19 criteria provided, single submitter clinical testing Variant summary: ATM c.4060C>A (p.Pro1354Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 248752 control chromosomes, predominantly at a frequency of 0.0004 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.001), allowing no conclusion about variant significance. However, in certain European subpopulations the variant occurs with an even higher frequency, e.g. in Southern Europeans 0.0012 (14/11412 alleles), suggesting that the variant could be a benign polymorphism. In addition, the variant was reported in 6 / 7325 European American women, who were older than age 70, and have never had cancer (in the FLOSSIES database). c.4060C>A has been reported in the literature in individuals affected with Breast Cancer and other tumor phenotypes, but was also repeatedly found in controls or non-cancer-related patient cohorts (e.g. Tavera-Tapia_2017, Tavtigian_2009, Bernstein_2010, Quezada Urban_2018, Tiao_2017, Fanale_2020, Urbina-Jara_2019, Kraemer_2019), providing no strong evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (7x), likely benign (1x) / benign (1x). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000656759 SCV001249803 uncertain significance not provided 2019-10-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000168271 SCV001262665 uncertain significance Ataxia-telangiectasia syndrome 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656759 SCV001469349 uncertain significance not provided 2019-10-17 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000656759 SCV001474794 uncertain significance not provided 2019-10-17 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000656759 SCV001713574 uncertain significance not provided 2020-11-25 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354169 SCV001548713 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Pro1354Thr variant was identified in a large-scale case control study in 1 of 5062 proband chromosomes (frequency: 0.0002) from individuals or families with breast cancer and was present in 1 of 4490 control chromosomes (frequency: 0.0002) from healthy individuals (Tavtigian-2009). The variant was identified in dbSNP (ID: rs145119475) as “With Uncertain significance” allele, ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae and University of Chicago). The variant was not identified in Cosmic, MutDB, LOVD 3.0, and ATM-LOVD databases. The variant was identified in control databases in 50 of 274452 chromosomes at a frequency of 0.0002 increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017) including 45 of 124128 European chromosomes and 1 of 6442 “other” chromosomes. The p.Pro1354Thr residue is not conserved in mammals, the threonine amino acid is found in mouse, African clawed frog, and zebrafish; and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, 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, 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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