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

gnomAD frequency: 0.00014  dbSNP: rs146017595

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165498	SCV000216229	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-19	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 alteration has been reported in at least one breast cancer patient 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, 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	RCV000206887	SCV000260024	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-28	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). RNA analysis indicates that this missense change has a conflicting impact on mRNA splicing. 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). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Studies have shown that this missense change results in conflicting data on mRNA splicing (PMID: 31811167; Invitae). 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	2023-09-18	criteria provided, single submitter	clinical testing	Observed in individuals with personal or family history of breast cancer (Decker et al., 2017; Dominguez-Valentin et al., 2019; Dorling et al., 2021; Bhai et al., 2021); 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 (Dominguez-Valentin et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28779002, 31811167, 33471991, 34326862)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590439	SCV000694266	uncertain significance	not provided	2016-06-20	criteria provided, single submitter	clinical testing	Variant summary: The ATM c.3806A>G (p.Lys1269Arg) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant was found in 3/120788 control chromosomes at a frequency of 0.0000248, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor evaluated for functional impact by in vivo/vitro studies. It has been reported by two labs in ClinVar without evidence to independently evaluate and they have classified it as uncertain significance. Because of the absence of sufficient clinical information and the lack of functional studies, the variant is currently classified as a variant of uncertain significance (VUS) until additional information becomes available.
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	2016-03-04	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	2023-09-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003895144	SCV004716754	uncertain significance	ATM-related condition	2024-02-05	criteria provided, single submitter	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.
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