Submissions for variant NM_000051.4(ATM):c.7875_7876delinsGC (p.Asp2625_Ala2626delinsGluPro)

dbSNP: rs267606668

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132184	SCV000187263	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-03	criteria provided, single submitter	clinical testing	The c.7875_7876delTGinsGC variant (also known as p.D2625_A2626delinsEP), located in coding exon 52 of the ATM gene, results from the deletion of TG and the insertion of GC at nucleotide positions 7875 and 7876. This causes amino acid substitutions at two highly-conserved codons: the aspartic acid at codon 2625 is replaced by glutamic acid and the alanine at codon 2626 is replaced by proline. This alteration has been reported in multiple ataxia-telangiectasia (AT) families, both homozygous and in trans with known pathogenic mutations (van Belzen MJ et al. Hum. Genet. 1998 Feb;102(2):187-91; Li A and Swift M. Am. J. Med. Genet. 2000 May;92(3):170-7; Becker-Catania SG et al. Mol. Genet. Metab. 2000 Jun; 70(2):122-33; Laake K et al. Hum. Mutat. 2000 Sep;16(3):232-46; Dörk T et al. Am. J. Med. Genet. A 2004 Apr;126A(3):272-7; Verhagen MM et al. Hum. Mutat. 2012 Mar;33(3):561-71; Driessen GJ et al. J. Allergy Clin. Immunol. 2013 May;131(5):1367-75.e9). In one study, this variant was associated with complete absence of ATM protein in one homozygous AT patient (Becker-Catania SG et al. Mol. Genet. Metab. 2000 Jun;70(2):122-33), while a second study detected ATM protein, but no ATM kinase activity in four homozygous AT patients (Verhagen MM et al. Hum. Mutat. 2012 Mar;33(3):561-71). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Counsyl	RCV000202436	SCV000486124	likely pathogenic	Ataxia-telangiectasia syndrome	2016-04-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000202436	SCV000546759	pathogenic	Ataxia-telangiectasia syndrome	2024-01-29	criteria provided, single submitter	clinical testing	This variant, c.7875_7876delinsGC, is a complex sequence change that results in the substitution of 2 amino acid(s) in the ATM protein (p.Asp2625_Ala2626delinsGluPro). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has been observed in individual(s) with ataxia telangiectasia (PMID: 9521587, 10980530, 19535770, 22213089). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as a double missense variant, D2625E and A2626P on the same chromosome. ClinVar contains an entry for this variant (Variation ID: 3030). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects ATM function (PMID: 22213089). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000132184	SCV000682438	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-11-01	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid and alanine at codons 2625 and 2626 of the ATM protein with glutamic acid and proline. This variant has been reported in the homozygous state or compound heterozygous state with another pathogenic ATM variant in individuals affected with ataxia telangiectasia (PMID: 9521587, 10873394, 11104561, 15054841, 17985259, 19535770, 21778326, 22213089, 25037873, 25122203, 30549301, 31050087). Cells derived from some of these individuals have shown reduced ATM kinase activity (PMID: 22213089, 30549301, 31050087). In a large international case-control study, this variant was reported in 8/60466 breast cancer cases and 7/53461 controls (PMID: 33471991). This variant has also been reported in an individual affected with pancreatic cancer (PMID: 29922827). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV000679143	SCV000805620	likely pathogenic	not provided	2016-04-26	criteria provided, single submitter	clinical testing
Mendelics	RCV000202436	SCV000838600	pathogenic	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000202436	SCV003929076	pathogenic	Ataxia-telangiectasia syndrome	2023-04-10	criteria provided, single submitter	clinical testing	Variant summary: ATM c.7875_7876delinsGC (p.Asp2625_Ala2626delinsGluPro) results in an in-frame deletion-insertion that is predicted to delete two amino acids and insert to amino acids from the encoded protein. The variant was absent in 250852 control chromosomes (gnomAD). c.7875_7876delinsGC has been reported in the literature in multiple bi-allelic individuals affected with Ataxia-Telangiectasia (example: Verhagen_2012). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Human Genetics Bochum, Ruhr University Bochum	RCV003333722	SCV004042764	pathogenic	Familial cancer of breast	2022-12-05	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant: PS4, PS3_MOD, PM3, PM2_SUP, PP3
Institute of Human Genetics, University Hospital of Duesseldorf	RCV003333722	SCV004171146	pathogenic	Familial cancer of breast		criteria provided, single submitter	not provided
Baylor Genetics	RCV003333722	SCV004207061	pathogenic	Familial cancer of breast	2024-03-05	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003333722	SCV004931105	likely pathogenic	Familial cancer of breast	2024-02-02	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9521587, 10980530, 19535770].
OMIM	RCV000202436	SCV000023327	pathogenic	Ataxia-telangiectasia syndrome	2004-04-30	no assertion criteria provided	literature only
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000202436	SCV000189490	not provided	Ataxia-telangiectasia syndrome		no assertion provided	not provided
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV003333722	SCV004041660	pathogenic	Familial cancer of breast	2023-10-09	no assertion criteria provided	clinical testing