ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1009C>T (p.Arg337Cys) (rs138398778)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 13
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656756 SCV000149039 uncertain significance not provided 2021-02-19 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with chronic lymphocytic leukemia, breast cancer, thyroid cancer, or prostate cancer (Broeks 2008, Zick 2015, Decker 2017, Tiao 2017, Isaacsson Velho 2018, Walsh 2018); This variant is associated with the following publications: (PMID: 27896999, 28569218, 28870692, 22529920, 17393301, 19781682, 22420423, 27720647, 24463458, 28500398, 27844328, 28779002, 29368341, 29449433, 23778141, 29872864, 28652578, 29106415, 29316426, 30197789, 30662270, 30814645, 30303537, 31843900, 30537493, 33280026, 30311369, 32183301)
Ambry Genetics RCV000115130 SCV000186506 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-17 criteria provided, single submitter clinical testing The p.R337C variant (also known as c.1009C>T), located in coding exon 7 of the ATM gene, results from a C to T substitution at nucleotide position 1009. The arginine at codon 337 is replaced by cysteine, an amino acid with highly dissimilar properties. Using multiple in silico tools, this alteration was predicted to have some potential for functional significance (Tavtigian SV et al. Am. J. Hum. Genet. 2009 Oct;85:427-46; George Priya Doss C et al. PLoS One. 2012 Apr;7:e34573). This alteration has also been reported in an patient with unilateral breast cancer diagnosed before 50 years of age and an individual with prostate cancer (Broeks A et al. Breast Cancer Res. Treat. 2008 Jan;107:243-8; Velho P et al. Prostate 2018 04;78(5):401-407). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be inconclusive by in silico analyses. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000168399 SCV000219092 uncertain significance Ataxia-telangiectasia syndrome 2020-10-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 337 of the ATM protein (p.Arg337Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs138398778, ExAC 0.01%). This variant has been observed in individual(s) with breast cancer and prostate cancer (PMID: 19781682, 17393301, 29368341). ClinVar contains an entry for this variant (Variation ID: 127327). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000656756 SCV000341173 uncertain significance not provided 2016-05-30 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115130 SCV000681943 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-14 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 337 of the ATM protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold ≤0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and prostate cancer (PMID: 17393301, 19781682, 20305132, 23555315, 28779002, 29368341), chronic lymphocytic leukemia (PMID: 28652578) and in unaffected controls (PMID: 28652578, 28779002). This variant has been identified in 26/282550 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
PreventionGenetics,PreventionGenetics RCV000656756 SCV000805487 uncertain significance not provided 2017-10-16 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780894 SCV000918528 uncertain significance not specified 2018-07-13 criteria provided, single submitter clinical testing Variant summary: ATM c.1009C>T (p.Arg337Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.2e-05 in 281750 control chromosomes. This frequency is not higher than expected for a pathogenic variant in ATM causing Breast Cancer (8.2e-05 vs 0.001), allowing no conclusion about variant significance. c.1009C>T has been reported in the literature in individuals affected with Breast Cancer without strong evidence for pathogenicity. Thus, these reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with other pathogenic variants have been reported (ATM - variant not specified (ClinVar); MSH2 c.2021G>A, p.Gly674Asp (internal LCA specimen)), providing supporting evidence for a benign role. 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 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics RCV000168399 SCV001138444 uncertain significance Ataxia-telangiectasia syndrome 2019-05-28 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000656756 SCV001143094 uncertain significance not provided 2021-02-03 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000168399 SCV001775531 uncertain significance Ataxia-telangiectasia syndrome 2021-08-03 criteria provided, single submitter clinical testing
King Laboratory,University of Washington RCV000780894 SCV001251385 benign not specified 2019-09-01 no assertion criteria provided research
Natera, Inc. RCV000168399 SCV001456876 uncertain significance Ataxia-telangiectasia syndrome 2020-09-16 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356891 SCV001552173 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Arg337Cys variant was identified in 1 of 874 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer (Broeks 2008). The variant was also identified in dbSNP (ID: rs138398778) as “With Uncertain significance allele”, in ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae, Color Genomics), Clinvitae, Cosmic, and MutDB databases. The variant was not identified in the COGR or LOVD 3.0 databases. The variant was identified in control databases in 23 of 276952 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 24020 chromosomes (freq: 0.00004), Other in 1 of 6460 chromosomes (freq: 0.0002), Latino in 6 of 34376 chromosomes (freq: 0.0002), European in 13 of 126526 chromosomes (freq: 0.0001), and South Asian in 2 of 30782 chromosomes (freq: 0.000065), it was not observed in the Ashkenazi Jewish, East Asian, or Finnish populations. The p.Arg337 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. 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. This variant is classified as a variant of uncertain significance.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.