Submissions for variant NM_000051.4(ATM):c.1703G>T (p.Arg568Ile)

gnomAD frequency: 0.00010  dbSNP: rs200381392

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129176	SCV000183911	likely benign	Hereditary cancer-predisposing syndrome	2018-11-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000416037	SCV000209690	likely benign	not provided	2021-03-17	criteria provided, single submitter	clinical testing	Observed in individuals with a personal and/or family history of melanoma, breast, ovarian, endometrial, colorectal or prostate cancer (Tung 2015, Decker 2017, Yurgelun 2017, Cock-Rada 2018, Paulo 2018, Pritchard 2018, Yehia 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26878173, 27997549, 28528518, 28135145, 28873162, 29641532, 28779002, 29684080, 28137924, 25186627, 29659569, 31658756)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195658	SCV000254062	benign	Ataxia-telangiectasia syndrome	2024-01-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000416037	SCV000493325	uncertain significance	not provided	2016-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129176	SCV000537515	likely benign	Hereditary cancer-predisposing syndrome	2020-08-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515396	SCV000611346	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2017-05-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000855571	SCV000694193	benign	not specified	2021-10-18	criteria provided, single submitter	clinical testing	Variant summary: ATM c.1703G>T (p.Arg568Ile) results in a non-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 0.00019 in 276984 control chromosomes, predominantly at a frequency of 0.0034 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.1703G>T has been reported in the literature in individuals affected with Colorectal cancer or prostate cancer (Yurgelun_2016, Paulo_2018). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with other pathogenic/likely pathogenic variants have been reported (ATM c.8934_8935del, p.E2979Afs*9; CHEK2 c.1283C>T, p.Ser428Phe, Yurgelun_2016 and internal data), providing supporting evidence for a benign role. Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Benign n=1, Likely benign n=4, VUS n=7). Based on the evidence outlined above, the variant was classified as benign.
Counsyl	RCV000195658	SCV000799739	uncertain significance	Ataxia-telangiectasia syndrome	2018-05-03	criteria provided, single submitter	clinical testing
Mendelics	RCV000195658	SCV000838492	uncertain significance	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000195658	SCV001266058	uncertain significance	Ataxia-telangiectasia syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000515396	SCV001468410	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2021-03-30	criteria provided, single submitter	clinical testing	ATM NM_000051.3 exon11 p.Arg568Ile (c.1703G>T): This variant has been reported in the literature in 1 individual with rectal cancer (Yurgelun 2017 PMID:28135145). This variant is present in 0.3% (36/10366) of Ashkenazi Jewish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/11-108122659-G-T?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:140916). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. Of note, an additional variant at this same amino acid position (p.Arg568Lys) was identified in a patient with a history of cervix and breast cancer. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Athena Diagnostics	RCV000855571	SCV001880881	likely benign	not specified	2020-09-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000416037	SCV002047328	likely benign	not provided	2020-09-21	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129176	SCV002531075	likely benign	Hereditary cancer-predisposing syndrome	2021-03-19	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000855571	SCV004027155	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000129176	SCV005045423	likely benign	Hereditary cancer-predisposing syndrome	2024-02-20	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004589621	SCV005083853	likely benign	Familial cancer of breast	2024-05-01	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].
Natera, Inc.	RCV000195658	SCV001461082	uncertain significance	Ataxia-telangiectasia syndrome	2020-01-11	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357003	SCV001552324	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Arg568Ile variant was identified in 1 of 170 proband chromosomes (frequency: 0.006) from individuals or families with breast and ovarian cancer (Cock-Rada 2017). The variant was also identified in the following databases: dbSNP (ID: rs200381392) as With Uncertain significance allele, ClinVar (classified as uncertain significance by Ambry Genetics, GenDx, Invitae) and Clinvitae. The variant was not identified in the COGR, Cosmic, MutDB, or LOVD 3.0 databases. The variant was identified in control databases in 54 of 276984 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency variant (Genome Aggregation Consortium Feb 27, 2017). The p.Arg568 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.