Submissions for variant NM_000051.4(ATM):c.1138T>A (p.Tyr380Asn)

gnomAD frequency: 0.00001  dbSNP: rs34083085

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000590112	SCV000149044	uncertain significance	not provided	2023-01-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer or rectal cancer, but also observed in healthy controls (Renwick et al., 2006; Tavtigian et al., 2009; Tung et al., 2015; Decker et al., 2017; Pearlman et al., 2017; Tiao et al., 2017); This variant is associated with the following publications: (PMID: 25186627, 22529920, 27978560, 19781682, 28779002, 16832357, 28652578)
Ambry Genetics	RCV000115135	SCV000172949	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-27	criteria provided, single submitter	clinical testing	The p.Y380N variant (also known as c.1138T>A), located in coding exon 8 of the ATM gene, results from a T to A substitution at nucleotide position 1138. The tyrosine at codon 380 is replaced by asparagine, an amino acid with dissimilar properties. This alteration has been detected in 0/4112 breast cancer patients and 1/2399 healthy control individuals across numerous studies (Tavtigian SV et al. Am J Hum Genet, 2009 Oct;85:427-46). This variant was observed in an individual with early onset-breast cancer amongst a cohort of 1781 non-Ashkenazi Jewish individuals undergoing BRCA1/2 gene testing based on a personal history of breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33). This alteration has been previously identified in an individual from a North American cohort of individuals with early onset colon cancer (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471). 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.
Invitae	RCV000464763	SCV000547112	likely benign	Ataxia-telangiectasia syndrome	2024-01-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590112	SCV000694171	uncertain significance	not provided	2017-04-20	criteria provided, single submitter	clinical testing	Variant summary: The ATM c.1138T>A (p.Tyr380Asn) variant involves the alteration of a non-conserved nucleotide, which results in a missense substitution at a residue that is not found within a known functional domain (InterPro). 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in the large control database ExAC and control cohorts at a frequency of 0.0000236 (3/126962 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). The variant has been cited in several publications, two of which identified control subjects carrying the variant (Tavtigian_AJHG_2009; Renwick_NatGenet_2006). In another study, the variant was identified in a patient diagnosed with rectal cancer, though no cosegregation data was included. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as one of uncertain significance. Taken together, this variant is classified as VUS until more occurrences in the general population are identified and functional impact is assessed.
Eurofins Ntd Llc (ga)	RCV000590112	SCV000701958	uncertain significance	not provided	2016-10-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115135	SCV000903114	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-07	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with asparagine at codon 380 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been identified in individuals affected with breast cancer (PMID: 28779002, 33471991), colorectal cancer (PMID: 27978560), and healthy controls (PMID: 16832357, 28779002, 33471991). This variant has been identified in 4/282678 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.
Natera, Inc.	RCV000464763	SCV002092735	uncertain significance	Ataxia-telangiectasia syndrome	2021-02-16	no assertion criteria provided	clinical testing