Submissions for variant NM_000051.4(ATM):c.4871A>G (p.His1624Arg)

gnomAD frequency: 0.00021  dbSNP: rs56354559

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000122854	SCV000166112	likely benign	Ataxia-telangiectasia syndrome	2024-01-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129349	SCV000184113	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-08	criteria provided, single submitter	clinical testing	The p.H1624R variant (also known as c.4871A>G), located in coding exon 31 of the ATM gene, results from an A to G substitution at nucleotide position 4871. The histidine at codon 1624 is replaced by arginine, an amino acid with highly similar properties. This alteration has been detected in 0/4,112 breast cancer patients and 1/2,399 healthy control individuals across numerous studies (Tavtigian S et al. Am J Hum Genet. 2009 Oct;85(4):427-46). In another study, this variant was reported in 1/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med 2021 02;384:428-439). This variant was identified in 6/3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This alteration has been reported in the germline of 4 of 8,920 ethnically matched normal population control subjects and in 0 of 516 samples from a study of chronic lymphocytic leukemia patients of European descent (Tiao G et al. Leukemia, 2017 Oct;31:2244-2247). This alteration has also been reported in an endometrial cancer patient from a cohort of 4034 cancer cases from The Cancer Genome Atlas (Lu C et al. Nat Commun. 2015 Dec 22;6:10086). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000587947	SCV000209743	uncertain significance	not provided	2023-06-26	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 26214590, 22529920, 19781682, 26689913, 11443540, 28652578, 29684080, 33471991, 31206626)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002223131	SCV000694293	uncertain significance	not specified	2023-10-13	criteria provided, single submitter	clinical testing	Variant summary: ATM c.4871A>G (p.His1624Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251378 control chromosomes, predominantly at a frequency of 0.00062 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Ataxia-Telangiectasia (6e-05 vs 0.004), allowing no conclusion about variant significance. c.4871A>G has been reported in the literature in individuals affected with breast/ovarian cancer or undertaking colorectal/prostate cancer panel testing without evidence for causality (examples: Weitzel_2019, Dorling_2021, Giri_2022, Pearlman_2021) and in controls (examples: Tavtigian 2009, Tiao 2017, Dorling_2021). 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: 33471991, 22529920, 35666082, 26214590, 26689913, 34250417, 19781682, 11443540, 28652578, 31206626, 33471991). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (uncertain significance: n=5 and likely benign:n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000129349	SCV000903140	likely benign	Hereditary cancer-predisposing syndrome	2020-08-27	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129349	SCV002535443	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-11	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587947	SCV002774777	uncertain significance	not provided	2022-12-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003945107	SCV004759413	uncertain significance	ATM-related condition	2024-02-15	criteria provided, single submitter	clinical testing	The ATM c.4871A>G variant is predicted to result in the amino acid substitution p.His1624Arg. This variant has been reported in patients with breast cancer (Table S3, Weitzel et al. 2019. PubMed ID: 31206626) as well as in controls without cancer (Thorstenson et al. 2001. PubMed ID 11443540; Table S2, Tavtigian et al. 2009. PubMed ID: 19781682). This variant has also been reported in a study of patients with Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations (Table S9, Yehia et al. 2018. PubMed ID: 29684080). This variant is reported in 0.068% of alleles in individuals of African descent in gnomAD and is has conflicting interpretations of likely benign and uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/135757/. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Natera, Inc.	RCV000122854	SCV001462341	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing