Submissions for variant NM_000051.4(ATM):c.3576G>A (p.Lys1192=)

gnomAD frequency: 0.00001  dbSNP: rs587776551

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165646	SCV000216383	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-01	criteria provided, single submitter	clinical testing	The c.3576G>A pathogenic mutation (also known as p.K1192K) is located in coding exon 23 of the ATM gene. This pathogenic mutation results from a G to A substitution at nucleotide position 3576. This nucleotide substitution does not change the lysine at codon 1192. However, this change occurs in the last base pair of coding exon 23 which makes it likely to have some effect on normal mRNA splicing. This alteration has been reported frequently in individuals with a clinical diagnosis of ataxia telangiectasia, and has been observed in the homozygous state in individuals with severe disease (Chessa L et al. Ann. Hum. Genet. 2009 Sep;73(Pt 5):532-9; Cavalieri S et al. Ann. Hum. Genet. 2008 Jan;72(Pt 1):10-8; Sandoval N et al. Hum. Mol. Genet. 1999 Jan;8:69-79). This alteration has been demonstrated to cause abnormal splicing, resulting in skipping of exon 23 (referred to as exon 26 in the literature) (Demuth I et al. Neurogenetics. 2011 Nov;12:273-82; Sandoval N et al. Hum. Mol. Genet. 1999 Jan;8:69-79). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Furthermore, several studies have shown that this alteration results in decreased/absent ATM protein expression and very low ATM kinase activity (Gilad S et al. Am. J. Hum. Genet. 1998 Mar;62:551-61; Demuth I et al. Neurogenetics. 2011 Nov;12:273-82; Sandoval N et al. Hum. Mol. Genet. 1999 Jan;8:69-79). This nucleotide position is highly conserved in available vertebrate species. Based on the available evidence, c.3576G>A is classified as a pathogenic mutation.
GeneDx	RCV000236731	SCV000293312	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing	Located at the last nucleotide of exon 24 (also known as exon 26 in the literature) and demonstrated to result in abnormal splicing leading to skipping of exon 24 and/or exon 24-25 (Sandoval et al., 1999; Teraoka et a., 1999; Demuth et al., 2011; Jacquemin et al., 2012); Published functional studies demonstrate a damaging effect: reduced or absent protein expression and kinase activity (Sandoval et al., 1999; Teraoka et al., 1999; Demuth et al., 2011; Jacquemin et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with breast cancer and other cancers (Prodosmo et al., 2016; Huang et al., 2018; Akcay et al., 2020; Asadollahi et al., 2020; Pastorino et al., 2020); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 21965147, 10873394, 16941484, 17124347, 9463314, 21665257, 16189143, 11382771, 22927201, 27664052, 17910737, 22071889, 12552559, 10330348, 9450906, 9792409, 9443866, 22213089, 11606401, 15503472, 19691550, 8845835, 30819809, 30620386, 9887333, 29625052, 31741144, 32658311, 32325837, 32748564, 26896183, 33624863, 27599564)
Counsyl	RCV000003174	SCV000485198	pathogenic	Ataxia-telangiectasia syndrome	2016-03-08	criteria provided, single submitter	clinical testing
Invitae	RCV000003174	SCV000546861	pathogenic	Ataxia-telangiectasia syndrome	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change affects codon 1192 of the ATM mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ATM protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs587776551, gnomAD 0.004%). This variant has been observed in individuals with ataxia-telangiectasia and early-onset breast and thyroid cancer (PMID: 8845835, 9887333, 17124347, 19691550, 22071889, 27599564). This variant is also known as 3403del174. ClinVar contains an entry for this variant (Variation ID: 3035). 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: 22071889). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 24, but is expected to preserve the integrity of the reading-frame (PMID: 9887333; Invitae). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000165646	SCV000682142	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-17	criteria provided, single submitter	clinical testing	This variant alters the conserved c.G at the last nucleotide position of exon 24 of the ATM gene. Splice site prediction tools suggest that this variant may impact RNA splicing. Functional RNA studies have shown that this variant causes an in-frame skipping of exon 24 (hence, known as 3403del174 and p.Ser1135_Lys1192del58 in the literature) or out-of-frame skipping of exons 24 and 25 (PMID: 9887333, 21965147). This variant has been shown to significantly affect protein stability and/or kinase activity (PMID: 9887333, 21965147, 22071889). This variant has been reported in multiple individuals and families affected with ataxia-telangiectasia and is recurrent in Turkish and Italian populations (PMID: 9792409, 9887333, 16941484, 17124347, 19691550, 22071889, 30819809, 31741144, 34107524, 35257272). This variant has also been reported in two individuals affected with breast cancer (PMID: 27599564, 29665859). This variant has been identified in 4/251126 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Mendelics	RCV000003174	SCV000838524	pathogenic	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000003174	SCV000916595	pathogenic	Ataxia-telangiectasia syndrome	2018-09-24	criteria provided, single submitter	clinical testing	Variant summary: ATM c.3576G>A (p.Lys1192Lys) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5 splicing donor site. Two predict the variant weakens a 5' donor site. An experimental study, Demuth_2011, supports these predictions by finding that this variant is associated with an in-frame exclusion of exon 26 from the mRNA. The variant allele was found at a frequency of 1.6e-05 in 246056 control chromosomes (gnomAD). The variant, c.3576G>A, has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (Chessa_2009, Demuth_2011). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000236731	SCV001249802	pathogenic	not provided	2019-05-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000236731	SCV001448074	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001797990	SCV002042132	pathogenic	Breast and/or ovarian cancer	2020-06-15	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000236731	SCV002760560	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV002467434	SCV002762774	pathogenic	Familial cancer of breast	2022-12-09	criteria provided, single submitter	research	PS3_MOD, PM3_VSTR
Institute of Human Genetics, University Hospital of Duesseldorf	RCV000003174	SCV004171155	likely pathogenic	Ataxia-telangiectasia syndrome		criteria provided, single submitter	not provided
Baylor Genetics	RCV002467434	SCV004210162	pathogenic	Familial cancer of breast	2023-07-13	criteria provided, single submitter	clinical testing
OMIM	RCV000003174	SCV000023332	pathogenic	Ataxia-telangiectasia syndrome	1999-01-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000003174	SCV001457151	pathogenic	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000236731	SCV001744656	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000236731	SCV001952013	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000236731	SCV002036130	likely pathogenic	not provided		no assertion criteria provided	clinical testing