Submissions for variant NM_000051.4(ATM):c.1139A>G (p.Tyr380Cys)

dbSNP: rs786203855

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167345	SCV000218197	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-05	criteria provided, single submitter	clinical testing	The p.Y380C variant (also known as c.1139A>G), located in coding exon 8 of the ATM gene, results from an A to G substitution at nucleotide position 1139. The tyrosine at codon 380 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is poorly conserved in available vertebrate species, and cysteine is the reference amino acid in multiple 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	RCV000696213	SCV000824765	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 380 of the ATM protein (p.Tyr380Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 187601). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV001193600	SCV001362539	uncertain significance	not specified	2019-03-21	criteria provided, single submitter	clinical testing	Variant summary: ATM c.1139A>G (p.Tyr380Cys) 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 was absent in 277070 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1139A>G in individuals affected with Ataxia-Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV000696213	SCV002092757	uncertain significance	Ataxia-telangiectasia syndrome	2021-02-26	no assertion criteria provided	clinical testing