Submissions for variant NM_000051.4(ATM):c.7880A>G (p.Tyr2627Cys)

gnomAD frequency: 0.00001  dbSNP: rs767670019

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000204776	SCV000260313	likely pathogenic	Ataxia-telangiectasia syndrome	2023-12-05	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 2627 of the ATM protein (p.Tyr2627Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and/or lung squamous cell carcinoma (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 220064). 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. This variant disrupts the p.Tyr2627 amino acid residue in ATM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22071889). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV000567581	SCV000660630	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-19	criteria provided, single submitter	clinical testing	The p.Y2627C variant (also known as c.7880A>G), located in coding exon 52 of the ATM gene, results from an A to G substitution at nucleotide position 7880. The tyrosine at codon 2627 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Mendelics	RCV000204776	SCV000838602	uncertain significance	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000567581	SCV002052779	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 2627 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 not been reported in individuals affected with hereditary cancer in the literature. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477687	SCV004222217	uncertain significance	not provided	2012-10-15	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMID: 35264596 (2022)) and lung squamous cell carcinoma (PMID: 26689913 (2015)). The frequency of this variant in the general population, 0.0000066 (1/152192 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
PreventionGenetics, part of Exact Sciences	RCV003897446	SCV004714477	uncertain significance	ATM-related condition	2024-01-02	criteria provided, single submitter	clinical testing	The ATM c.7880A>G variant is predicted to result in the amino acid substitution p.Tyr2627Cys. This variant was reported in an individual with breast cancer and an individual with squamous cell lung carcinoma (Table S3, Guindalini et al. 2022. PubMed ID: 35264596; Supplementary Data 12, Lu et al. 2015. PubMed ID: 26689913). This variant has not been reported in a large population database, indicating this variant is rare. It has conflicting interpretations of likely pathogenic and uncertain in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/220064/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Natera, Inc.	RCV000204776	SCV002075932	uncertain significance	Ataxia-telangiectasia syndrome	2021-02-10	no assertion criteria provided	clinical testing