ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7618G>A (p.Val2540Ile) (rs35203200)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130162 SCV000184998 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-09 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000167957 SCV000218605 uncertain significance Ataxia-telangiectasia syndrome 2019-01-09 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 2540 of the ATM protein (p.Val2540Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs35203200, ExAC 0.009%). This variant has been reported in individuals affected with gastric cancer (PMID: 26689913), breast cancer (PMID: 26976419), ovarian cancer (PMID: 28591191) and colorectal cancer (PMID: 27978560). However, this variant has also been reported to have no association with cancer in a small case-control study that included 2,531 individuals with breast cancer and 2,245 controls (PMID: 19781682). ClinVar contains an entry for this variant (Variation ID: 141579). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
GeneDx RCV000236319 SCV000292819 uncertain significance not provided 2018-07-18 criteria provided, single submitter clinical testing This variant is denoted ATM c.7618G>A at the cDNA level, p.Val2540Ile (V2540I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). This variant has been reported in individuals with breast, ovarian, gastric, or rectal cancer, but was also observed in unaffected controls (Tavtigian 2009, Lu 2015, Pearlman 2016, Tung 2016, Decker 2017, Stafford 2017, Hauke 2018). ATM Val2540Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the FAT domain (Stracker 2013). 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 Val2540Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000167957 SCV000799397 uncertain significance Ataxia-telangiectasia syndrome 2018-04-17 criteria provided, single submitter clinical testing
Color RCV000130162 SCV000902974 likely benign Hereditary cancer-predisposing syndrome 2015-12-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779778 SCV000916568 uncertain significance not specified 2019-04-18 criteria provided, single submitter clinical testing Variant summary: ATM c.7618G>A (p.Val2540Ile) results in a conservative amino acid change located in the PIK-related kinase, FAT domain of 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 4.8e-05 in 252044 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4.8e-05 vs 0.004), allowing no conclusion about variant significance. c.7618G>A has been reported in the literature in individuals affected with breast cancer, ovarian cancer, chronic lymphocytic leukemia, rectal cancer, pancreatic cancer and prostate cancer (Dudley_2018, Hauke_2018, Stafford_2017, Tiao_2017, Pearlman_2016, Tung_2016, Tung_2015) but also in unaffected controls (Renwick_2006, Tavtigian_2009). These reports do not provide unequivocal conclusions about association of the variant either with Ataxia-Telangiectasia or with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000236319 SCV001148444 uncertain significance not provided 2019-01-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000167957 SCV001157876 uncertain significance Ataxia-telangiectasia syndrome 2018-09-28 criteria provided, single submitter clinical testing The ATM c.7618G>A; p.Val2540Ile variant (rs35203200) is reported in the literature in individuals with breast, ovarian, stomach, or colorectal cancer (Lu 2015, Pearlman 2017, Stafford, Tung 2016) but has also been reported in an unaffected control (Tavtigian 2009). This variant is classified as uncertain in ClinVar (Variation ID: 141579), and found in the general population with an overall allele frequency of 0.005% (13/276580 alleles) in the Genome Aggregation Database. The valine at codon 2540 is moderately conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Lu C et al. Patterns and functional implications of rare germline variants across 12 cancer types. Nat Commun. 2015 Dec 22;6:10086. Pearlman R et al. Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer. JAMA Oncol. 2017 Apr 1;3(4):464-471. Stafford JL et al. Reanalysis of BRCA1/2 negative high risk ovarian cancer patients reveals novel germline risk loci and insights into missing heritability. PLoS One. 2017 Jun 7;12(6):e0178450. Tavtigian SV et al. Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer. Am J Hum Genet. 2009 Oct;85(4):427-46. Tung N et al. Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer. J Clin Oncol. 2016 May 1;34(13):1460-8.

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