Submissions for variant NM_000051.4(ATM):c.7408T>G (p.Tyr2470Asp)

dbSNP: rs876659365

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220077	SCV000275741	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-03-28	criteria provided, single submitter	clinical testing	The p.Y2470D variant (also known as c.7408T>G), located in coding exon 49 of the ATM gene, results from a T to G substitution at nucleotide position 7408. The tyrosine at codon 2470 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This alteration has been reported in multiple patients with ataxia telangiectasia (A-T) including one patient who was homozygous for this variant (Sandoval N, Hum. Mol. Genet. 1999 Jan; Chessa L, Ann. Hum. Genet. 2009 Sep; 73(Pt 5):532-9; 8(1):69-79; Micol R et al. J Allergy Clin Immunol, 2011 Aug;128:382-9.e1; Zannolli R et al. Mov Disord, 2012 Sep;27:1312-6; Prodosmo A, J. Clin. Invest. 2013 Mar; 123(3):1335-42). This alteration was also detected in a cohort of 523 Italian male breast cancer patients screened by a multigene custom panel of 50 cancer-associated genes (Rizzolo P et al. Int J Cancer, 2019 07;145:390-400). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000528764	SCV000622744	pathogenic	Ataxia-telangiectasia syndrome	2023-02-03	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 231789). This missense change has been observed in individual(s) with ataxia-telangiectasia (PMID: 9887333, 19691550, 21665257). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 2470 of the ATM protein (p.Tyr2470Asp).
Counsyl	RCV000528764	SCV000788870	likely pathogenic	Ataxia-telangiectasia syndrome	2016-12-21	criteria provided, single submitter	clinical testing
Mendelics	RCV002247654	SCV002518540	pathogenic	Familial cancer of breast	2022-05-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002247654	SCV004210222	pathogenic	Familial cancer of breast	2023-06-29	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002247654	SCV004932212	likely pathogenic	Familial cancer of breast	2024-01-31	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: 9887333, 19691550, 21665257].