Submissions for variant NM_000051.4(ATM):c.1516G>T (p.Gly506Cys)

gnomAD frequency: 0.00004  dbSNP: rs587779816

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000211963	SCV000149052	likely benign	not provided	2021-04-28	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25318351, 27997549, 26786923, 32172615, 24123366, 28652578, 32325837)
Ambry Genetics	RCV000115143	SCV000215651	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-17	criteria provided, single submitter	clinical testing	The p.G506C variant (also known as c.1516G>T), located in coding exon 9 of the ATM gene, results from a G to T substitution at nucleotide position 1516. The glycine at codon 506 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was reported as homozygous in a Saudi female with onset of ataxia telangiectasia (A-T) at age 14 with classic neurodegenerative symptoms clinically and on imaging but without immune system dysfunction or endocrine abnormalities. Another affected sister was also homozygous for this alteration, while three heterozygous family members did not have features of A-T (Algahtani H et al. Int J Neurosci, 2020 Mar;:1-6). This variant has also been identified in individuals with breast cancer and in one proband with cutaneous melanoma (Decker B et al. J Med Genet, 2017;54:732-741; Hauke J et al. Cancer Medicine, 2018;7(4):1349-1358; Pastorino L et al. Cancers, 2020 04;12(4):1007; Guglielmi C et al. Int J Mol Sci, 2021 Jul;22). This alteration was seen in a total of 11/61,198 breast cancer cases as well as 6/53,951 controls across two studies (Akcay IM et al. Int J Cancer, 2021 01;148:285-295; Dorling et al. N Engl J Med. 2021 02;384:428-439). In another study, this alteration was reported in the germline of 5 of 8,920 ethnically matched normal population control subjects but was not seen in 516 samples from a study of chronic lymphocytic leukemia patients of European descent (Tiao G et al. Leukemia, 2017 10;31:2244-2247). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000168231	SCV000218900	likely benign	Ataxia-telangiectasia syndrome	2024-01-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115143	SCV000537575	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-01	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with cysteine at codon 506 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 an individual with bilateral breast cancer (PMID: 34299313). In a large international case-control study, this variant was reported in 8/60458 breast cancer cases and 4/53457 controls (OR=1.768, 95%CI 0.532 to 5.873, p-value=0.399; PMID: 33471991). A report by Algahtani et al, 2021 (PMID: 32172615) identified this variant in the homozygous state in a Saudi female with onset of atypical ataxia-telangiectasia at 14 years old. This individual had slow disease progression with neurodegenerative symptoms but no immune system deficiencies and normal endocrine function. Her sister was also homozygous for this variant and exhibited similar atypical ataxia-telangiectasia symptoms with disease onset at 16 years old. Their parents were first degree cousin, had no symptoms, and were heterozygous for this variant. The proband had 8 unaffected siblings, one of whom was genotyped and shown to be heterozygous for this variant. This variant has also been identified in 11/282626 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.
Fulgent Genetics, Fulgent Genetics	RCV000515225	SCV000611344	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2017-05-23	criteria provided, single submitter	clinical testing
Mendelics	RCV000168231	SCV000838490	uncertain significance	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000211963	SCV001747024	uncertain significance	not provided	2021-06-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818258	SCV002070879	uncertain significance	not specified	2020-06-11	criteria provided, single submitter	clinical testing	DNA sequence analysis of the ATM gene demonstrated a sequence change, c.1516G>T, in exon 10 that results in an amino acid change, p.Gly506Cys. This sequence change does not appear to have been previously described in patients with ATM-related disorders and has been described in the gnomAD database with a frequency of 0.007% in the European sub-population (dbSNP rs587779816). The p.Gly506Cys change affects a moderately conserved amino acid residue located in a domain of the ATM protein that is not known to be functional. The p.Gly506Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Gly506Cys change remains unknown at this time.
Sema4, Sema4	RCV000115143	SCV002532705	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-17	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV000168231	SCV003827473	uncertain significance	Ataxia-telangiectasia syndrome	2022-05-02	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149791	SCV003837596	uncertain significance	Breast and/or ovarian cancer	2021-10-05	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003237336	SCV003936038	uncertain significance	Familial cancer of breast	2023-06-06	criteria provided, single submitter	clinical testing	a variant of uncertain significance in the ATM gene (p.Gly506Cys). This sequence change replaces glycine with cysteine at codon 506 of the ATM protein (p.Gly506Cys). The glycine residue is moderately conserved and there is a large physicochemical difference between glycine and cysteine. This variant has been reported in the literature in individuals with ATM-related disease (PMID 32172615, 32325837). ClinVar contains an entry for this variant (Variation ID: 127339) with 6 submissions: 1 likely benign and 5 uncertain significance, conflicting interpretations. In-silico predictions for this varint show Pathogenic computational verdict based on 7 pathogenic predictions from DANN, EIGEN, FATHMM-MKL, M-CAP, MutationAssessor, MutationTaster and SIFT vs 5 benign predictions from BayesDel_addAF, DEOGEN2, LIST-S2, MVP and PrimateAI. for these reasons, this variant has been classified as a Variant of Uncertain Significance. Pathogenic mutations in the ATM gene cause autosomal dominant Susceptibility to Breast Cancer (OMIM 114480).
PreventionGenetics, part of Exact Sciences	RCV003407490	SCV004114947	uncertain significance	ATM-related condition	2023-07-11	criteria provided, single submitter	clinical testing	The ATM c.1516G>T variant is predicted to result in the amino acid substitution p.Gly506Cys. This variant has been reported in the homozygous state in two siblings with ataxia telangiectasia (Algahtani et al. 2021. PubMed ID: 32172615). This variant has been reported in patients with colorectal, breast or ovarian cancer, and melanoma (Table A4, Yurgelun et al. 2017. PubMed ID: 28135145; File S2, Howitt et al. 2014. PubMed ID: 25231023; Cock-Rada et al. 2018. PubMed ID: 28528518, Pastorino et al. 2020. PubMed ID: 32325837), but was also reported in three healthy control individuals in a study of patients with chronic lymphocytic leukemia (Table S6, Tiao et al. 2017. PubMed ID: 28652578). This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108121708-G-T) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127339/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000211963	SCV004219978	uncertain significance	not provided	2020-11-06	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00007 (9/129046 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 28779002 (2017), 29522266 (2018), 34299313 (2021), 35264596 (2022)) and melanoma (PMID: 32325837 (2020)). The variant has also been reported in the homozygous state in two individuals of a family with ataxia-telangiectasia (A-T) (PMID: 32172615 (2020)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.