Submissions for variant NM_000051.4(ATM):c.6145T>G (p.Tyr2049Asp)

dbSNP: rs786203767

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167214	SCV000218051	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-10-25	criteria provided, single submitter	clinical testing	The p.Y2049D variant (also known as c.6145T>G), located in coding exon 41 of the ATM gene, results from a T to G substitution at nucleotide position 6145. The tyrosine at codon 2049 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This variant has been identified in individuals with ataxia telangiectasia (Podralska MJ et al. Mol Genet Genomic Med. 2014 Nov;2:504-11; Maciejczyk M et al. Front Immunol, 2019 Sep;10:2322). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV000523725	SCV000616646	uncertain significance	not provided	2017-10-25	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.6145T>G at the cDNA level, p.Tyr2049Asp (Y2049D) at the protein level,and results in the change of a Tyrosine to an Aspartic Acid (TAT>GAT). This variant was observed in the compoundheterozygous state with another ATM variant in a pediatric patient with ataxia-telangiectasia (Podralska 2014). ATMTyr2049Asp was not observed in large population cohorts (Lek 2016). Since Tyrosine and Aspartic Acid differ inpolarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATMTyr2049Asp occurs at a position that is conserved across species and is located within the FAT domain (Stracker2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based oncurrently available information, it is unclear whether ATM Tyr2049Asp is pathogenic or benign. We consider it to be avariant of uncertain significance
Labcorp Genetics (formerly Invitae), Labcorp	RCV000628069	SCV000748958	uncertain significance	Ataxia-telangiectasia syndrome	2023-11-07	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 2049 of the ATM protein (p.Tyr2049Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ataxia telangiectasia (PMID: 25614872). ClinVar contains an entry for this variant (Variation ID: 187481). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Counsyl	RCV000628069	SCV000797277	uncertain significance	Ataxia-telangiectasia syndrome	2018-01-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000167214	SCV001734075	uncertain significance	Hereditary cancer-predisposing syndrome	2020-08-20	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with aspartic acid at codon 2049 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed as a heterozygous variant in an individual affected with ataxia-telangiectasia (PMID: 25614872). This variant has not been identified 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330526	SCV004037663	uncertain significance	not specified	2023-08-29	criteria provided, single submitter	clinical testing	Variant summary: ATM c.6145T>G (p.Tyr2049Asp) results in a non-conservative amino acid change located in the PIK-related kinase domain (IPR014009) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251404 control chromosomes. c.6145T>G has been reported in the literature as a biallelic compound heterozygous genotype in at-least three individuals affected with Ataxia-Telangiectasia as well as a VUS in settings of multigene panel testing among individuals with a variety of cancers (example, Podralska_2014, Maciejczyk_2019, Seligson_2019, Moens_2014, Pearlman_2021). These data indicate that the variant may be associated with disease. 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: 31611883, 25502423, 34250417, 25614872, 30541756). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV003483552	SCV004231817	likely pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-09	criteria provided, single submitter	curation	. According to the ACMG standard criteria we chose these criteria: PM2 (supporting pathogenic): Absent from controls , PM3 (strong pathogenic): found in trans in AT-patients: Maciejczyk et al und Podralska et al., PP3 (supporting pathogenic): REVEL: 0,83
Baylor Genetics	RCV004567335	SCV005057043	likely pathogenic	Familial cancer of breast	2024-01-26	criteria provided, single submitter	clinical testing