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

gnomAD frequency: 0.00001  dbSNP: rs34083085

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000590112	SCV000149044	uncertain significance	not provided	2024-08-07	criteria provided, single submitter	clinical testing	Observed in individuals with breast cancer or rectal cancer, but also observed in healthy controls (PMID: 16832357, 19781682, 25186627, 28779002, 27978560, 28652578, 33471991); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25186627, 22529920, 27978560, 19781682, 28779002, 16832357, 28652578, 33471991)
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.
Labcorp Genetics (formerly Invitae), Labcorp	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	RCV004767076	SCV000694171	uncertain significance	not specified	2024-08-20	criteria provided, single submitter	clinical testing	Variant summary: ATM c.1138T>A (p.Tyr380Asn) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.9e-05 in 257124 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1138T>A has been reported in the literature in individuals affected with Breast Cancer or Colorectal Cancer, as well as unaffected controls (e.g. Tung_2015, Pearlman_2016, Dorling_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19781682, 22529920, 16832357, 27978560, 33471991, 25186627). ClinVar contains an entry for this variant (Variation ID: 127331). Based on the evidence outlined above, the variant was classified as uncertain significance.
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.
Myriad Genetics, Inc.	RCV004589554	SCV005083835	likely benign	Familial cancer of breast	2024-04-25	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Natera, Inc.	RCV000464763	SCV002092735	uncertain significance	Ataxia-telangiectasia syndrome	2021-02-16	no assertion criteria provided	clinical testing