Submissions for variant NM_000051.4(ATM):c.8560C>T (p.Arg2854Cys)

gnomAD frequency: 0.00013  dbSNP: rs201958469

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131002	SCV000185927	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-03	criteria provided, single submitter	clinical testing	The p.R2854C variant (also known as c.8560C>T), located in coding exon 57 of the ATM gene, results from a C to T substitution at nucleotide position 8560. The arginine at codon 2854 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration is located in the phosphatidylinositol 3-kinase (PI3K) domain and has been reported in one individual from a cohort of 122 breast cancer patients (Pagila LL et al. Breast Cancer Res. Treat. 2010 Jan;119:443-52). This variant also was identified in 1/882 Chinese individuals who underwent multi-gene panel testing for HBOC risk assessment (Shao D et al. Cancer Sci, 2020 Feb;111:647-657) and in two women of European ancestry who were diagnosed with breast cancer before age 50 (Tung N et al. Cancer, 2015 Jan;121:25-33). This alteration has also been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). 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.
GeneDx	RCV000656765	SCV000209659	uncertain significance	not provided	2023-10-03	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 a personal or family history of melanoma, breast, ovarian, colorectal, pancreatic, or other cancers (Paglia et al., 2010; Tung et al., 2015; de Voer et al., 2016; Decker et al., 2017; Yurgelun et al., 2017; Martin-Morales et al., 2018; Rizzolo et al., 2019; Earl et al., 2020; Shao et al., 2020; Dalmasso et al., 2021; Laraqui et al., 2021; Bhai et al., 2021; Okawa et al., 2023); This variant is associated with the following publications: (PMID: 19404735, 25801821, 26901136, 28717660, 27043212, 28611190, 28135145, 28495793, 28779002, 29659569, 25186627, 30256826, 31159747, 30303537, 32113160, 31590326, 33054100, 33471991, 32522261, 26580448, 30613976, 28652578, 34646395, 31742824, 20305132, 34262154, 23532176, 36243179, 35264596, 34326862)
Eurofins Ntd Llc (ga)	RCV000656765	SCV000231411	uncertain significance	not provided	2015-03-30	criteria provided, single submitter	clinical testing
Invitae	RCV000199741	SCV000254156	benign	Ataxia-telangiectasia syndrome	2024-01-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131002	SCV000537553	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 2854 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer, colorectal cancer and prostate cancer (PMID: 19404735, 20305132, 23555315, 26901136, 28135145, 28779002, 29659569, 30256826, 34646395, 33471991). This variant has also been identified in 49/282448 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.
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000585658	SCV000693456	uncertain significance	Familial cancer of breast	2017-08-07	criteria provided, single submitter	clinical testing	This missense variant in the ATM gene was identified in a female patient with breast cancer at 45 years, and a familial history of breast cancer: 2 maternal cousins, 2 maternal aunts, one maternal grand-mother and one paternal cousin.
PreventionGenetics, part of Exact Sciences	RCV003891667	SCV000805628	uncertain significance	ATM-related condition	2024-01-12	criteria provided, single submitter	clinical testing	The ATM c.8560C>T variant is predicted to result in the amino acid substitution p.Arg2854Cys. This variant was reported in two individuals with breast cancer (Paglia et al. 2009. PubMed ID: 19404735, Table 1; Girard et al. 2018. PubMed ID: 30303537, Table S3), four individuals with colorectal cancer (de Voer et al. 2016. PubMed ID: 26901136, Table S3; Yurgelun et al. 2017. PubMed ID: 28135145, Table A4), an individual with prostate cancer (Paulo et al. 2018. PubMed ID: 29659569, Table 2), and an individual undergoing hereditary cancer testing (Tsaousis et al. 2019. PubMed ID: 31159747, Table S5). It has also been observed in a case and multiple controls from a chronic lymphocytic leukemia cohort (Tiao et al. 2017. PubMed ID: 28652578, Table S6). At PreventionGenetics, this variant has been observed in an individual with a family history of cancer who harbored a BRIP1 nonsense variant (internal data). This variant is reported in 0.045% of alleles in individuals of Latino descent in gnomAD and is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142147/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
GeneKor MSA	RCV000131002	SCV000821880	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000199741	SCV000838618	uncertain significance	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000656765	SCV000840965	uncertain significance	not provided	2022-11-08	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools predict that this variant is damaging.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779783	SCV000916576	uncertain significance	not specified	2023-10-02	criteria provided, single submitter	clinical testing	Variant summary: ATM c.8560C>T (p.Arg2854Cys) results in a non-conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain (IPR000403) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 255074 control chromosomes, predominantly at a frequency of 0.00046 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (0.0002 vs 0.001), allowing no conclusion about variant significance. c.8560C>T has been reported in the literature in individuals affected with breast cancer, colorectal cancer, chronic lymphocytic leukemia, prostate cancer, Lynch syndrome and melanoma (e.g. LaPaglia_ 2009, Bernstein_2010, Tung_2014, deVoer2016, Yurgelun_2017, Tiao_2017, Paulo_2018, Martin-Morales_2018, Girard_2019, Rizzolo_2019, Tsaousis_2019, Velzquez_2020, Daimasso_2021). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrence with another pathogenic variant has been reported (CHEK2 c.1232G>A, p.W411*, internal data), providing supporting evidence for a benign role. In addition, this variant was found in one healthy older woman in a reputed germline gnomic database (FLOSSIES). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19404735, 20305132, 25186627, 26901136, 28135145, 28717660, 26580448, 28652578, 30256826, 29659569, 30303537, 31159747, 30613976, 34262154, 32522261). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=13) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
CeGaT Center for Human Genetics Tuebingen	RCV000656765	SCV001148452	uncertain significance	not provided	2022-12-01	criteria provided, single submitter	clinical testing	ATM: PP3
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798447	SCV002042295	uncertain significance	Breast and/or ovarian cancer	2023-03-13	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131002	SCV002529912	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-16	criteria provided, single submitter	curation
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000585658	SCV003807077	uncertain significance	Familial cancer of breast	2022-08-02	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2 supporting, PP3 supporting
Baylor Genetics	RCV000585658	SCV004200681	uncertain significance	Familial cancer of breast	2023-10-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656765	SCV004222275	uncertain significance	not provided	2022-11-08	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00045 (16/35400 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 28779002 (2017), 30303537 (2019), 30613976 (2019), 32522261 (2020), 34646395 (2021)), colorectal cancer (PMID: 26901136 (2016), 28135145 (2017), 30256826 (2018)), chronic lymphocytic leukemia (PMID: 28652578 (2017)), and pancreatic cancer (PMID: 32113160 (2020)). It has also been reported in unaffected individuals (PMID: 28779002 (2017), 33471991 (2021)). 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. The frequency of this variant in the general population, 0.00045 (16/35400 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 28779002 (2017), 30303537 (2019), 30613976 (2019), 32522261 (2020), 34646395 (2021)), colorectal cancer (PMID: 26901136 (2016), 28135145 (2017), 30256826 (2018)), chronic lymphocytic leukemia (PMID: 28652578 (2017)), and pancreatic cancer (PMID: 32113160 (2020)). It has also been reported in unaffected individuals (PMID: 28779002 (2017), 33471991 (2021)). 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354297	SCV001548878	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The ATM p.Arg2854Cys variant was identified in 1 of 3258 proband chromosomes (frequency: 0.0003) from individuals or families with breast and/or ovarian cancer and tested negative for BRCA1 and BRCA2 (Paglia 2010). The variant was also identified in the following databases: dbSNP (ID: rs201958469) as “With Uncertain significance allele”, in ClinVar (5x, as uncertain significance by Ambry Genetics, GeneDx, EGL Genetics, Invitae, Color Genomics), and Clinvitae (4x, as uncertain significance by ClinVar, Invitae and EmvClass). The variant was not identified in Cosmic, MutDB, LOVD 3.0, or ATM-LOVD databases. The variant was identified in control databases in 50 of 276788 chromosomes at a frequency of 0.000181 in the following populations: “other” in 4 of 6456 chromosomes (freq. 0.00061), Latino in 16 of 34376 chromosomes (freq. 0.00046), European in 26 of 126370 chromosomes (freq. 0.0002), Finnish in 3 of 25782 chromosomes (freq. 0.00011), and South Asian in 1 of 30778 chromosomes (freq. 0.000032) (Genome Aggregation Consortium Feb 27, 2017). Although the p.Arg2854 residue is not conserved in mammals, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the arginine 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357714	SCV001553265	uncertain significance	Papillary thyroid carcinoma		no assertion criteria provided	clinical testing	The ATM p.Arg2854Cys variant was identified in 1 of 3258 proband chromosomes (frequency: 0.0003) from individuals or families with breast and/or ovarian cancer and tested negative for BRCA1 and BRCA2 (Paglia 2010). The variant was also identified in the following databases: dbSNP (ID: rs201958469) as “With Uncertain significance allele”, in ClinVar (5x, as uncertain significance by Ambry Genetics, GeneDx, EGL Genetics, Invitae, Color Genomics), and Clinvitae (4x, as uncertain significance by ClinVar, Invitae and EmvClass). The variant was not identified in Cosmic, MutDB, LOVD 3.0, or ATM-LOVD databases. The variant was identified in control databases in 50 of 276788 chromosomes at a frequency of 0.000181 in the following populations: “other” in 4 of 6456 chromosomes (freq. 0.00061), Latino in 16 of 34376 chromosomes (freq. 0.00046), European in 26 of 126370 chromosomes (freq. 0.0002), Finnish in 3 of 25782 chromosomes (freq. 0.00011), and South Asian in 1 of 30778 chromosomes (freq. 0.000032) (Genome Aggregation Consortium Feb 27, 2017). Although the p.Arg2854 residue is not conserved in mammals, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the arginine 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.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000656765	SCV001906082	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000656765	SCV001953723	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000656765	SCV001974366	uncertain significance	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000656765	SCV002036023	uncertain significance	not provided		no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV003483503	SCV004228829	not provided	Familial cancer of breast; Ataxia-telangiectasia syndrome		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 03-07-2016 by Lab Ambry Genetics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.