Submissions for variant NM_000051.4(ATM):c.692A>G (p.His231Arg)

gnomAD frequency: 0.00001  dbSNP: rs587782229

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130924	SCV000185836	uncertain significance	Hereditary cancer-predisposing syndrome	2024-12-30	criteria provided, single submitter	clinical testing	The p.H231R variant (also known as c.692A>G), located in coding exon 6 of the ATM gene, results from an A to G substitution at nucleotide position 692. The histidine at codon 231 is replaced by arginine, an amino acid with highly similar properties. In one study, this alteration was detected in 1/4112 breast cancer patients and 0/2399 healthy control individuals (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85(4):427-46). This alteration was also reported in a cohort of 270 Austrian HBOC families previously screened for BRCA1 and BRCA2 mutations (Thorstenson YR et al. Cancer Res, 2003 Jun;63:3325-33). This variant was also detected in an Italian individual with classic ataxia telangiectasia; however, a second alteration was not identified (Magliozzi M et al. Dis. Markers. 2006;22(4):257-64). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
GeneDx	RCV000423648	SCV000512134	uncertain significance	not provided	2024-11-12	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17124347, 19781682, 12810666, 33471991, 35534704)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000457349	SCV000547151	uncertain significance	Ataxia-telangiectasia syndrome	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 231 of the ATM protein (p.His231Arg). This variant is present in population databases (rs587782229, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer and/or clinical features of ataxia-telangiectasia (PMID: 12810666, 17124347, 19781682, 35534704). ClinVar contains an entry for this variant (Variation ID: 142096). 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%. 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.
Color Diagnostics, LLC DBA Color Health	RCV000130924	SCV000682377	uncertain significance	Hereditary cancer-predisposing syndrome	2024-12-17	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with arginine at codon 231 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals or families affected with breast cancer (PMID: 12810666, 19781682, 33471991). The variant has also been observed heterozygous in an individual affected with ataxia-telangiectasia, but without a known second mutation (PMID: 17124347). This variant has been identified in 4/251096 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.
Counsyl	RCV000457349	SCV000789627	uncertain significance	Ataxia-telangiectasia syndrome	2017-02-08	criteria provided, single submitter	clinical testing
Mendelics	RCV000457349	SCV000838475	uncertain significance	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000457349	SCV001262434	uncertain significance	Ataxia-telangiectasia syndrome	2017-09-13	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Fulgent Genetics, Fulgent Genetics	RCV002492509	SCV002779435	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2021-12-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467160	SCV004210122	uncertain significance	Familial cancer of breast	2024-03-09	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital	RCV004776276	SCV005382077	uncertain significance	Diffuse midline glioma, H3 K27-altered		criteria provided, single submitter	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV003467160	SCV005919227	uncertain significance	Familial cancer of breast	2023-12-13	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000457349	SCV002085902	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-21	no assertion criteria provided	clinical testing