Submissions for variant NM_000051.4(ATM):c.1634C>T (p.Ala545Val)

gnomAD frequency: 0.00001  dbSNP: rs878853485

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000227629	SCV000282875	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 545 of the ATM protein (p.Ala545Val). This variant is present in population databases (no rsID available, gnomAD 0.002%). 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: 236675). 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 tolerated. 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.
Ambry Genetics	RCV001012386	SCV001172826	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-01	criteria provided, single submitter	clinical testing	The p.A545V variant (also known as c.1634C>T), located in coding exon 10 of the ATM gene, results from a C to T substitution at nucleotide position 1634. The alanine at codon 545 is replaced by valine, an amino acid with similar properties. This amino acid position is highly 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.
Color Diagnostics, LLC DBA Color Health	RCV001012386	SCV001341305	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-13	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 545 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. In a large international case-control study, this variant was reported in 1/60466 breast cancer cases and 1/53461 controls (OR=0.884, 95%CI 0.055 to 14.136; PMID: 33471991). This variant has been identified in 2/251288 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.
GeneDx	RCV001589166	SCV001826323	uncertain significance	not provided	2020-06-23	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Sema4, Sema4	RCV001012386	SCV002530976	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-27	criteria provided, single submitter	curation
Baylor Genetics	RCV003469121	SCV004210341	uncertain significance	Familial cancer of breast	2023-05-26	criteria provided, single submitter	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001589166	SCV002037328	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001589166	SCV002037714	likely benign	not provided		no assertion criteria provided	clinical testing