Submissions for variant NM_000051.4(ATM):c.2519A>T (p.Asp840Val)

gnomAD frequency: 0.00003  dbSNP: rs786202605

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165495	SCV000216226	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-11	criteria provided, single submitter	clinical testing	The p.D840V variant (also known as c.2519A>T), located in coding exon 16 of the ATM gene, results from an A to T substitution at nucleotide position 2519. The aspartic acid at codon 840 is replaced by valine, an amino acid with highly dissimilar properties. This variant has been detected in a patient with a personal and/or family history of cancer who presented for cancer genetic counseling (Cabanillas R et al. Mol Genet Genomic Med. 2017 Jul;5:336-359). This alteration was also detected in 2/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000459754	SCV000546871	uncertain significance	Ataxia-telangiectasia syndrome	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 840 of the ATM protein (p.Asp840Val). This variant is present in population databases (rs786202605, gnomAD 0.0009%). 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: 185978). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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.
Color Diagnostics, LLC DBA Color Health	RCV000165495	SCV000687393	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-25	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with valine at codon 840 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 been reported in an individual affected with breast cancer (PMID: 29522266). This variant has been identified in 2/251410 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.
PreventionGenetics, part of Exact Sciences	RCV000679104	SCV000805519	uncertain significance	not provided	2017-10-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000679104	SCV001786379	uncertain significance	not provided	2019-11-25	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in an individual undergoing multi-gene cancer panel testing based on personal and/or family history (Cabanillas 2017); This variant is associated with the following publications: (PMID: 28717660)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000679104	SCV002010838	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000679104	SCV002585345	uncertain significance	not provided	2022-09-01	criteria provided, single submitter	clinical testing	ATM: PM1:Strong, BP4
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150023	SCV003837835	uncertain significance	Breast and/or ovarian cancer	2022-03-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003468746	SCV004211986	uncertain significance	Familial cancer of breast	2023-12-19	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000459754	SCV002080257	uncertain significance	Ataxia-telangiectasia syndrome	2021-03-05	no assertion criteria provided	clinical testing