Submissions for variant NM_000051.4(ATM):c.3806A>G (p.Lys1269Arg)

gnomAD frequency: 0.00012  dbSNP: rs146017595

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165498	SCV000216229	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-23	criteria provided, single submitter	clinical testing	The p.K1269R variant (also known as c.3806A>G), located in coding exon 25 of the ATM gene, results from an A to G substitution at nucleotide position 3806. The lysine at codon 1269 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206887	SCV000260024	uncertain significance	Ataxia-telangiectasia syndrome	2024-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 1269 of the ATM protein (p.Lys1269Arg). This variant is present in population databases (rs146017595, gnomAD 0.008%). This missense change has been observed in individual(s) with breast cancer (PMID: 31811167, 34326862). ClinVar contains an entry for this variant (Variation ID: 185981). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000590439	SCV000564632	uncertain significance	not provided	2025-05-19	criteria provided, single submitter	clinical testing	Published functional studies suggest this variant may impact splicing resulting in several aberrant transcripts, but the effect was not complete as some full length transcript was also present in a mini gene assay (PMID: 31811167); In silico analysis suggests that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with personal or family history of breast cancer (PMID: 28779002, 31811167, 33471991, 34326862); This variant is associated with the following publications: (PMID: 28779002, 31811167, 33471991, 34326862)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700508	SCV000694266	uncertain significance	not specified	2024-06-28	criteria provided, single submitter	clinical testing	Variant summary: ATM c.3806A>G (p.Lys1269Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Two predict the variant strengthens a cryptic 5' donor site. One predict the variant creates a 5' donor site. In a cell-based minigene assay, the variant showed aberrant splicing (Dominguez-Valentin_2019), however the in vivo implication of these studies is not known. The variant allele was found at a frequency of 2.4e-05 in 251238 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3806A>G has been reported in the literature in individuals affected with breast cancer and prostate cancer (examples: Bhai_2021, Dominguez-Valentin_2019, Mateo_2020). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. 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: 28779002, 34326862, 31811167, 36315919, 31874108). ClinVar contains an entry for this variant (Variation ID: 185981). Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000206887	SCV000789440	uncertain significance	Ataxia-telangiectasia syndrome	2017-02-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763700	SCV000894580	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165498	SCV000902910	likely benign	Hereditary cancer-predisposing syndrome	2024-09-18	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798592	SCV002042167	uncertain significance	Breast and/or ovarian cancer	2019-05-30	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000165498	SCV002536617	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-01	criteria provided, single submitter	curation
Baylor Genetics	RCV003462176	SCV004207099	uncertain significance	Familial cancer of breast	2024-03-06	criteria provided, single submitter	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV004764775	SCV005374670	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-08-13	criteria provided, single submitter	curation	According to the ClinGen ACMG ATM v1.3.0 criteria we chose this criterion: PVS1 (supporting pathogenic): Abberant splicing in minigene Assay PMID: 31811167
Athena Diagnostics	RCV000590439	SCV005622622	uncertain significance	not provided	2024-11-14	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 uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive (PMID 31811167).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590439	SCV005622986	uncertain significance	not provided	2024-06-13	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000206887	SCV001458193	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000590439	SCV001742600	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000590439	SCV001954570	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004552911	SCV004716754	uncertain significance	ATM-related disorder	2024-02-05	no assertion criteria provided	clinical testing	The ATM c.3806A>G variant is predicted to result in the amino acid substitution p.Lys1269Arg. This variant has been reported in an individual with breast cancer who has a family history of breast, ovarian, and colorectal cancer (Dominguez-Valentin et al. 2019. PubMed ID: 31811167). In this same study, this variant was shown to lead to aberrant splicing leading to an in-frame deletion using an in vitro minigene assay. No RNA from the patient was available to test splicing effects as an in vivo experiment. ATM levels in the patient’s tumor were weak-to-absent. This variant has also been reported in additional individuals with personal and/or family histories of breast cancer (Table S5, Decker et al. 2017. PubMed ID: 28779002; Table S4, Bhai et al. 2021. PubMed ID: 34326862). This variant was reported in 10 cases in one large study of individuals with breast cancer; however, it was also reported in 3 controls in that study (Dorling et al. 2021. PubMed ID: 33471991). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/185981/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.