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

gnomAD frequency: 0.00019  dbSNP: rs147187700

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000223979	SCV000149126	uncertain significance	not provided	2024-10-21	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16014569, 19781682, 21787400, 16832357, 21933854, 25503501, 25980754, 26580448, 25925381, 28971906, 29909963, 29522266, 25186627, 28779002, 28652578, 31843900, 9764584, 33471991, 33436325, 19431188, 35980532, 35534704, 34326862, 34262154)
Ambry Genetics	RCV000115217	SCV000184428	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-01	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, this alteration has been observed in multiple cancer cohorts and control groups (Tavtigian SV et al. Am. J. Hum. Genet. 2009 Oct;85:427-46; Skowronska A et al. Haematologica. 2012 Jan;97:142-6; Tung N et al. Cancer. 2015 Jan;121:25-33; Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346; Decker B et al. J Med Genet. 2017 11;54:732-741; Hauke J et al. Cancer Med. 2018 04;7:1349-1358; Karlsson Q et al. Eur Urol Oncol, 2021 Aug;4:570-579). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167876	SCV000218522	likely benign	Ataxia-telangiectasia syndrome	2024-02-01	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 Diagnostics, LLC DBA Color Health	RCV000115217	SCV000537538	likely benign	Hereditary cancer-predisposing syndrome	2021-08-19	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
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	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	likely benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing	Variant summary: ATM c.5821G>C (p.Val1941Leu) results in a conservative amino acid change located in the PIK-related kinase 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 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 estimated for a pathogenic variant in ATM causing breast/ATM-related cancer and/or Ataxia Telangiectasia. 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 (e.g. Shayeghi_1998, Renwick_2006, Maxwell_2015, Pereira_2022), other tumor phenotypes such as chronic lymphocytic leukemia (CLL), Lynch syndrome-associated cancer and/or polyps, pediatric low grade glioma (e.g. Skowronska_2011, Yurgelun_2015, Zhang_2015, Tung_2015) and also in several healthy controls (e.g. Tavtigian_2009, Skowronska_2011, Tiao_2017, Yu_2022). Recent case-control studies showed that the frequencies of this variant are similar in cases (breast cancer, prostate cancer, or pancreatic cancer) and controls, indicating this variant does not associate with breast, prostate, or pancreatic cancer (Dorling_2021, Karlsson_2021, Yu_2022). Furthermore, a co-occurrence with another pathogenic variant (BRCA1 c.3607C>T, p.Arg1203X) has been observed for this variant (internal sample). 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), yet no significant decrease in specific kinase activity (Barone_2009). The following publications have been ascertained in the context of this evaluation (PMID: 19431188, 33471991, 33436325, 25503501, 35980532, 16832357, 9764584, 21933854, 19781682, 28652578, 25186627, 29909963, 35047863, 25980754, 26580448). ClinVar contains an entry for this variant (Variation ID: 127412). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000223979	SCV001148436	uncertain significance	not provided	2024-07-01	criteria provided, single submitter	clinical testing	ATM: PS3:Supporting
Illumina Laboratory Services, 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	2021-08-11	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000223979	SCV001471583	uncertain significance	not provided	2020-05-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001293033	SCV001481400	uncertain significance	Familial cancer of breast	2024-03-29	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001293033	SCV001737479	uncertain significance	Familial cancer of breast	2023-05-23	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/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function. A functional study has shown reduced ATM protein level and kinase activity (PMID: 19431188). This variant has been identified in individuals with breast cancer (PMID: 16832357, 25186627, 28779002, 29522266, 35980532), 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). This variant is present 10x in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Sema4, Sema4	RCV000115217	SCV002531743	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-07	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149795	SCV003837821	uncertain significance	Breast and/or ovarian cancer	2022-10-20	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001293033	SCV005083990	likely benign	Familial cancer of breast	2024-05-24	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Mayo Clinic Laboratories, Mayo Clinic	RCV000223979	SCV005412467	uncertain significance	not provided	2024-05-21	criteria provided, single submitter	clinical testing
Academic Department of Medical Genetics, University of Cambridge	RCV000115217	SCV000992202	likely pathogenic	Hereditary cancer-predisposing syndrome	2018-01-26	flagged submission	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.
King Laboratory, University of Washington	RCV000780923	SCV001251388	benign	not specified	2019-09-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004739394	SCV005352555	uncertain significance	ATM-related disorder	2024-08-13	no assertion criteria provided	clinical testing	The ATM c.5821G>C variant is predicted to result in the amino acid substitution p.Val1941Leu. This variant has been identified in individuals with breast cancer (Table S2, Renwick et al. 2006. PubMed ID: 16832357; Table S1, Maxwell et al. 2015. PubMed ID: 25503501, Table S4, Bhai et al. 2021. PubMed ID: 34326862), chronic lymphocytic leukemia (Table S2, Skowronska et al. 2012. PubMed ID: 21933854), and suspected Lynch syndrome (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754). Functional analysis showed that this variant results in reduced ATM protein activity (Barone et al. 2009. PubMed ID: 19431188). However, in case-control studies, this variant was identified with similar frequencies between controls and individuals with breast cancer or chronic lymphocytic leukemia (Table S2, Tavtigian et al. 2009. PubMed ID: 19781682; Table S2, Skowronska et al. 2012. PubMed ID: 21933854). This variant is reported in 0.025%of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar ranging from benign to uncertain (http://www.ncbi.nlm.nih.gov/clinvar/variation/127412). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.