Submissions for variant NM_000051.4(ATM):c.3772C>A (p.His1258Asn)

dbSNP: rs587782741

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132246	SCV000187329	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-03	criteria provided, single submitter	clinical testing	The p.H1258N variant (also known as c.3772C>A), located in coding exon 25 of the ATM gene, results from a C to A substitution at nucleotide position 3772. The histidine at codon 1258 is replaced by asparagine, an amino acid with similar properties. This alteration was also detected on a 25-gene panel test in a woman of African ancestry who was diagnosed with breast cancer before age 50 (Tung N et al, 2015 Jan;121:25-33). This amino acid position is not 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000471942	SCV000547007	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 1258 of the ATM protein (p.His1258Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 142817). 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. 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	RCV000478016	SCV000564631	uncertain significance	not provided	2014-12-22	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.3772C>A at the cDNA level, p.His1258Asn (H1258N) at the protein level, and results in the change of a Histidine to an Asparagine (CAT>AAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM His1258Asn was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Histidine and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. ATM His1258Asn occurs at a position that is moderately conserved across species and is not located in a known functional domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether ATM His1258Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000132246	SCV000687501	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-09	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000132246	SCV002536606	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-19	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003237339	SCV003936022	uncertain significance	Familial cancer of breast	2023-06-06	criteria provided, single submitter	clinical testing	A variant of uncertain significance was detected in the ATM gene (c.3772C>A). This sequence change replaces histidine with asparagine at codon 1258 of the ATM protein (p.His1258Asn). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and asparagine. This variant is not present in population databases (gnomAD). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 142817) with 7 submissions, all of which describe this variant as of uncertain significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). Therefore, it has been classified as a Variant of Uncertain Significance. Heterozygous pathogenic/likely pathogenic mutations in the ATM cause susceptibility to breast cancer (OMIM# 114480).
Baylor Genetics	RCV003237339	SCV004215509	uncertain significance	Familial cancer of breast	2023-05-24	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357095	SCV001552445	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.His1258Asn variant was not identified in the literature nor was it identified in the LOVD 3.0 database. The variant was identified in dbSNP (ID: rs587782741) as "With uncertain significance allele" and in ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx and Color). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The p.His1258 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Natera, Inc.	RCV000471942	SCV002079048	uncertain significance	Ataxia-telangiectasia syndrome	2020-03-16	no assertion criteria provided	clinical testing