Submissions for variant NM_000051.4(ATM):c.200A>G (p.Tyr67Cys)

dbSNP: rs754033733

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213607	SCV000275181	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-25	criteria provided, single submitter	clinical testing	The p.Y67C variant (also known as c.200A>G), located in coding exon 3 of the ATM gene, results from an A to G substitution at nucleotide position 200. The tyrosine at codon 67 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was detected in 2/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). This alteration was also identified in a patient with autoimmune lymphoproliferative syndrome (ALPS) -like phenotype (Grossi A et al. Genes (Basel), 2021 Aug;12:). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Genetic Services Laboratory, University of Chicago	RCV000501575	SCV000593493	uncertain significance	not specified	2016-04-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000556463	SCV000622302	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-21	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 67 of the ATM protein (p.Tyr67Cys). This variant is present in population databases (rs754033733, gnomAD 0.003%). 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: 231354). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. 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.
Color Diagnostics, LLC DBA Color Health	RCV000213607	SCV001349949	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-09	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 67 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/248620 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.
Division of Medical Genetics, University of Washington	RCV001250443	SCV001424819	uncertain significance	Familial cancer of breast	2019-04-01	criteria provided, single submitter	clinical testing	To our knowledge, this sequence variant has not been previously reported in the literature. The c.200A>G variant has an overall allele frequency of 0.000004 in the Broad Institute ExAC Browser (http://exac.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk.
GeneDx	RCV001548023	SCV001767868	uncertain significance	not provided	2023-06-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in the heterozygous state in an individual with breast cancer and among a cohort of patients affected with inborn errors of immunity (Hauke et al., 2018; Grossi et al., 2021); This variant is associated with the following publications: (PMID: 34573280, 29522266)
Baylor Genetics	RCV001250443	SCV004210077	uncertain significance	Familial cancer of breast	2023-08-05	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001250443	SCV005081993	likely benign	Familial cancer of breast	2024-04-18	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.	RCV000556463	SCV001461813	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing