ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1138T>A (p.Tyr380Asn) (rs34083085)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000590112 SCV000149044 uncertain significance not provided 2018-11-23 criteria provided, single submitter clinical testing This variant is denoted ATM c.1138T>A at the cDNA level, p.Tyr380Asn (Y380N) at the protein level, and results in the change of a Tyrosine to an Asparagine (TAC>AAC). This variant was observed in individuals with breast cancer or rectal cancer, but has also been observed in healthy controls (Renwick 2006, Tavtigian 2009, Tung 2015, Decker 2017, Pearlman 2017, Tiao 2017). ATM Tyr380Asn was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Tyr380Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115135 SCV000172949 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-10 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 alteration was also detected in 1/450 patients with colorectal cancer diagnosed before age 50 and was called a variant of uncertain significance (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 uncertain significance Ataxia-telangiectasia syndrome 2020-10-29 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with asparagine at codon 380 of the ATM protein (p.Tyr380Asn). The tyrosine residue is weakly conserved and there is a large physicochemical difference between tyrosine and asparagine. This variant is present in population databases (rs34083085, ExAC 0.002%). This variant has been reported in an individual affected with colorectal cancer (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 127331). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000590112 SCV000701958 uncertain significance not provided 2016-10-08 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115135 SCV000903114 likely benign Hereditary cancer-predisposing syndrome 2015-01-13 criteria provided, single submitter clinical testing

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