Submissions for variant NM_000051.4(ATM):c.1009C>T (p.Arg337Cys)

gnomAD frequency: 0.00017  dbSNP: rs138398778

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656756	SCV000149039	uncertain significance	not provided	2024-09-27	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 breast, prostate, pancreatic, and other cancers, but also in unaffected controls (PMID: 17393301, 28779002, 28652578, 29368341, 30311369, 34477817, 35047863, 36315919, 34262154, 34326862, 33471991, 33436325); 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, 31843900, 30537493, 33280026, 30311369, 32183301, 30303537, 34477817, 35047863, 36315919, 34262154, 34326862, 38451242, 33471991, 33436325, 37626821)
Ambry Genetics	RCV000115130	SCV000186506	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-20	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 been reported in an individual 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 alteration has also been reported both in affected cancer individuals and in unaffected controls across several studies (Decker B et al. J Med Genet, 2017 11;54:732-741; Tiao G et al. Leukemia, 2017 10;31:2244-2247; Girard E et al. Int J Cancer, 2019 04;144:1962-1974). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168399	SCV000219092	likely benign	Ataxia-telangiectasia syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000656756	SCV000341173	uncertain significance	not provided	2016-05-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115130	SCV000681943	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 337 of the ATM protein. Computational prediction 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, 34477817), chronic lymphocytic leukemia (PMID: 28652578) and in unaffected controls (PMID: 28652578, 28779002). In addition, a large international case-control study reported this variant in 4/60462 breast cancer cases and 10/53451 controls (OR=0.354, 95%, CI 0.111 to 1.128, p-value=0.105; PMID: 33471991). 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, part of Exact Sciences	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	2023-08-18	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 0.000092 (i.e. 26 heterozygotes) in 282550 control chromosomes gnomAD. This frequency is not higher than the estimated maximum expected for a pathogenic variant in ATM causing Breast Cancer (0.001), allowing no conclusion about variant significance. c.1009C>T has been reported in the literature in numerous individuals affected with Breast Cancer and other tumor phenotypes that belong to the HBOC cancer spectrum (e.g. Broeks_2008, Tavtigian_2009, Bernstein_2010, Karlsson_2021, Elbracht_2021), however, it was also reported in controls (Karlsson_2021). In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 4/60466 cases, but was also found in 10/53461 controls (Dorling_2021 through LOVD). At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (MSH2 c.2021G>A, p.Gly674Asp), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function and no occurrence of the variant in individuals affected with Ataxia-Telangiectasia has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20305132, 17393301, 33471991, 34477817, 33280026, 26085511, 33436325, 36315919, 27322425, 19781682, 28652578). Multiple submitters have reported clinical-significance assessments for this variant to ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant with a predominant consensus as VUS (n=13); two submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Mendelics	RCV000168399	SCV001138444	uncertain significance	Ataxia-telangiectasia syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000656756	SCV001143094	uncertain significance	not provided	2021-02-03	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000168399	SCV001775531	uncertain significance	Ataxia-telangiectasia syndrome	2021-08-03	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000656756	SCV002010851	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115130	SCV002529629	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-05	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV001762215	SCV002580517	uncertain significance	Familial cancer of breast	2021-12-28	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000780894	SCV004024384	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001762215	SCV004171463	uncertain significance	Familial cancer of breast	2023-10-16	criteria provided, single submitter	clinical testing	The ATM c.1009C>T (p.Arg337Cys) missense change has a maximum subpopulation frequency of 0.019% 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, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with breast cancer (PMID: 19781682, 30303537). 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.
Baylor Genetics	RCV001762215	SCV004206466	uncertain significance	Familial cancer of breast	2024-03-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656756	SCV004219891	uncertain significance	not provided	2021-02-03	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals affected with breast cancer (PMIDs: 17393301 (2008), 28569218 (2017), 28779002 (2017), 30537493 (2018), 30303537 (2019)), prostate cancer (PMID: 29368341 (2018)), and chronic lymphocytic leukemia (PMID: 28652578 (2017)), as well as unaffected controls (PMIDs: 28779002 (2017), 30303537 (2019)). It has also been reported in individuals with breast cancer as well as in unaffected controls in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/ATM)). The frequency of this variant in the general population, 0.0002 (7/35394 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115130	SCV005045429	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-27	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.