ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.5821G>C (p.Val1941Leu) (rs147187700)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Ambry Genetics RCV000115217 SCV000184428 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-06 criteria provided, single submitter clinical testing ​The p.V1941L variant (also known as c.5821G>C), located in coding exon 38 of the ATM gene, results from a G to C substitution at nucleotide position 5821. The valine at codon 1941 is replaced by leucine, an amino acid with highly similar properties. One functional analysis of this variant showed an associated reduction, but not absence, of ATM kinase activity (Barone G et al. Hum. Mutat. 2009 Aug;30:1222-30). Across numerous studies, the p.V1941L alteration was observed in 2/4112 breast cancer cases and 1/2399 control individuals (Tavtigian SV et al. Am. J. Hum. Genet. 2009 Oct;85:427-46). In addition, in a study examining patients with chronic lymphocytic leukemia, <span style="background-color:initial">this alteration was identified in <span style="background-color:initial">2/281 controls and 2/178 CLL patients without 11q deletion (Skowronska A et al. <span style="background-color:initial">Haematologica. 2012 Jan;97:142-6)<span style="background-color:initial">. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000167876 SCV000218522 likely benign Ataxia-telangiectasia syndrome 2020-12-06 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 Health, Inc RCV000115217 SCV000537538 uncertain significance Hereditary cancer-predisposing syndrome 2021-02-18 criteria provided, single submitter clinical testing This missense variant replaces valine with leucine at codon 1941 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant leads to reduced ATM kinase activity in a cell-based assay (PMID: 19431188). This variant has been reported in multiple individuals affected with breast cancer (PMID: 16832357, 19781682, 25503501) and chronic lymphocytic leukemia (PMID: 21933854). A meta-analysis was inconclusive regarding the association of this variant with breast cancer risk (PMID: 19781682). This variant has been observed in several healthy control individuals in the literature (PMID: 19781682, 28652578, 29909963), as well as in 10 women over age 70 with no personal history of cancer (FLOSSIES; https://whi.color.com/). This variant has been identified in 36/282434 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this variant has been reported in multiple individuals affected with breast cancer, as well as in healthy controls. 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.
Fulgent Genetics,Fulgent Genetics RCV000515219 SCV000611367 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
Counsyl RCV000167876 SCV000795616 uncertain significance Ataxia-telangiectasia syndrome 2017-11-10 criteria provided, single submitter clinical testing
Mendelics RCV000167876 SCV000838559 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000223979 SCV000840946 uncertain significance not provided 2018-03-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780923 SCV000918576 uncertain significance not specified 2019-07-10 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 0.00013 in 251056 control chromosomes, predominantly at a frequency of 0.00026 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.00013 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 (FLOSSIES database), which might suggest a benign outcome for the variant. c.5821G>C has been reported in the literature in individuals affected with Breast Cancer (Shayeghi 1998, Renwick 2006, Maxwell 2015) , other tumor phenotypes such as chronic lymphocytic leukemia (CLL), Lynch syndrome-associated cancer and/or polyps , pediatric low grade glioma (Skowronska 2011, Yurgelun 2015, Zhang 2015, Tung_2015) and also in several healthy controls (Skowronska 2011, Tiao 2017, Tavtigian_2009). These reports therefore do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrence with another pathogenic variant has been reported for this variant (BRCA1 c.3607C>T, p.Arg1203X, internal sample), which further supports its role as a benign variant. Using an ATM-null lymphoblastoid cell line (LCL) transfected with the variant of interest, Barone et al demonstrated an approximately 50% decrease in protein expression (or stability) but no significant decrease in specific kinase activity (Barone 2009). Nine ClinVar submissions (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000223979 SCV001148436 uncertain significance not provided 2018-09-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000167876 SCV001262766 uncertain significance Ataxia-telangiectasia syndrome 2017-08-16 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 RCV000223979 SCV001469356 uncertain significance not provided 2020-03-06 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285190 SCV001471583 uncertain significance none provided 2020-05-05 criteria provided, single submitter clinical testing
Baylor Genetics RCV001293033 SCV001481400 uncertain significance Familial cancer of breast 2020-02-23 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000167876 SCV001737479 uncertain significance Ataxia-telangiectasia syndrome 2021-05-27 criteria provided, single submitter clinical testing The ATM c.5821G>C (p.Val1941Leu) missense change has a maximum subpopulation frequency of 0.025% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/11-108180945-G-C?dataset=gnomad_r2_1). In silico tools are not in agreement about the effect of this variant on protein function, however functional studies has shown reduced ATM protein level and kinase activity (PS3_Supporting; PMID: 19431188). This variant has been identified in individuals with breast cancer (PMID: 28779002, 25186627, 29522266, 16832357), an individual undergoing clinical genetic testing for Lynch syndrome (PMID: 25980754), and an individual with multiple primary tumors or with a single primary tumor and a first-degree relative with multiple primary tumors (PMID: 29909963). In addition, in case-control studies the variant was present at similar or low frequencies in breast cancer patients compared to control subjects (PMID: 19781682, 28779002). It is also present 10x in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (BS2; https://whi.color.com/variant/11-108180945-G-C). To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PS3_Supporting, BS2.
King Laboratory,University of Washington RCV000780923 SCV001251388 benign not specified 2019-09-01 no assertion criteria provided research

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