Submissions for variant NM_000051.4(ATM):c.2189G>A (p.Cys730Tyr)

gnomAD frequency: 0.00002  dbSNP: rs587781595

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129658	SCV000184456	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-15	criteria provided, single submitter	clinical testing	The p.C730Y variant (also known as c.2189G>A), located in coding exon 13 of the ATM gene, results from a G to A substitution at nucleotide position 2189. The cysteine at codon 730 is replaced by tyrosine, an amino acid with highly dissimilar properties. 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.
Invitae	RCV000167916	SCV000218564	uncertain significance	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 730 of the ATM protein (p.Cys730Tyr). This variant is present in population databases (rs587781595, gnomAD 0.01%). 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: 141238). 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.
Fulgent Genetics, Fulgent Genetics	RCV000515399	SCV000611349	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2017-05-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129658	SCV000682038	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-03	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 730 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 performed for this variant. In a large international case-control study, this variant was reported in 1/60466 breast cancer cases and 1/53461 controls (PMID: 33471991). This variant has been identified in 3/282594 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.
Illumina Laboratory Services, Illumina	RCV000167916	SCV001260417	uncertain significance	Ataxia-telangiectasia syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Sema4, Sema4	RCV000129658	SCV002534210	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-21	criteria provided, single submitter	curation
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV003387507	SCV004099020	uncertain significance	not provided	2023-08-03	criteria provided, single submitter	clinical testing	BP4
PreventionGenetics, part of Exact Sciences	RCV004551244	SCV004117728	uncertain significance	ATM-related disorder	2022-12-01	criteria provided, single submitter	clinical testing	The ATM c.2189G>A variant is predicted to result in the amino acid substitution p.Cys730Tyr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108127006-G-A) and is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/141238/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
GeneDx	RCV003387507	SCV004168007	uncertain significance	not provided	2023-06-25	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; Identified in individual(s) with breast cancer and also in unaffected control(s) (Dorling et al., 2021); This variant is associated with the following publications: (PMID: 33471991)
Natera, Inc.	RCV000167916	SCV002077131	uncertain significance	Ataxia-telangiectasia syndrome	2021-03-19	no assertion criteria provided	clinical testing