ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5821G>C (p.Val1941Leu) (rs147187700)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Academic Department of Medical Genetics, University of Cambridge RCV000115217 SCV000992202 likely pathogenic Hereditary cancer-predisposing syndrome 2018-01-26 criteria provided, single submitter research Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.
Ambry Genetics RCV000115217 SCV000184428 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Athena Diagnostics Inc RCV000223979 SCV000840946 uncertain significance not provided 2018-03-21 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000223979 SCV000280993 uncertain significance not provided 2016-01-18 criteria provided, single submitter clinical testing Converted during submission to Uncertain significance.
Color RCV000115217 SCV000537538 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-11 criteria provided, single submitter clinical testing
Counsyl RCV000167876 SCV000795616 uncertain significance Ataxia-telangiectasia syndrome 2017-11-10 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515219 SCV000611367 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000223979 SCV000149126 uncertain significance not provided 2018-12-10 criteria provided, single submitter clinical testing This variant is denoted ATM c.5821G>C at the cDNA level, p.Val1941Leu (V1941L) at the protein level, and results in the change of a Valine to a Leucine (GTT>CTT). ATM Val1941Leu has been reported in individuals with breast cancer, glioma, or a Lynch related-cancer and/or polyps undergoing multigene hereditary cancer testing (Maxwell 2015, Tung 2015, Yurgelun 2015, Zhang 2015, Hauke 2018), and on functional interrogation, demonstrated reduced ATM protein level and kinase activity (Barone 2009). However, in two large case-control studies ATM Val1941Leu was present at similar or lower frequencies in breast cancer patients compared to control subjects (Tavtigian 2009, Decker 2017). In addition, this variant was present at similar or lower frequencies in cases vs. controls in two chronic lymphocytic leukemia case-control studies (Skowronska 2012, Tiao 2017). ATM Val1941Leu was observed at an allele frequency of 0.02% (29/126,446) in individuals of European ancestry in large population cohorts (Lek 2016). This variant 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 Val1941Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000780923 SCV000918576 uncertain significance not specified 2018-11-20 criteria provided, single submitter clinical testing Variant summary: ATM c.5821G>C (p.Val1941Leu) results in a 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 8.3e-05 in 121016 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ATM causing Breast Cancer (8.3e-05 vs 0.001), allowing no conclusion about variant significance. However, the variant was also reported in 10 / 9884 women (i.e. with a frequency of about 0.001), who were older than 70 years of age, and never had cancer (in the FLOSSIES database), which might support a benign role for the variant. c.5821G>C has been reported in the literature in individuals affected with Breast Cancer (Shayeghi 1998, Renwick 2006, Maxwell 2015) and other tumor phenotypes, such as chronic lymphocytic leukemia (CLL), Lynch syndrome-associated cancer and/or polyps and pediatric low grade glioma (Skowronska 2011, Yurgelun 2015, Zhang 2015), on the other hand it was also reported in several healthy controls (Skowronska 2011, Tiao 2017). These reports thus do not provide unequivocal conclusions about association of the variant with Breast Cancer. However, in a case-control study the variant was found at comparable frequencies in breast cancer cases (2/2531) and controls (1/2245), supporting a benign role for the variant (Tavtigian 2009). Furthermore, this variant has not been reported in families or individuals affected with Ataxia Telangectasia. On the other hand, one publication reported experimental evidence evaluating an impact on protein function, and demonstrated about 50% decrease in protein expression (or stability) in a transfected ATM-null lymphoblastoid cell line (LCL), but without a significant decrease in the specific kinase activity (Barone 2009). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000167876 SCV000218522 uncertain significance Ataxia-telangiectasia syndrome 2018-12-23 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 1941 of the ATM protein (p.Val1941Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs147187700, ExAC 0.02%). This variant has been reported in individuals affected with breast cancer (PMID: 19781682, 16832357, 25503501), chronic lymphocytic leukemia (PMID: 21933854), and suspected Lynch syndrome (PMID: 25980754). However, in a large meta-analysis this variant was not associated with an increased risk of breast cancer (PMID: 19781682). ClinVar contains an entry for this variant (Variation ID: 127412). Experimental studies have shown that this missense change leads to reduced ATM kinase activity (PMID: 19431188). 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.
Mendelics RCV000167876 SCV000838559 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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