Submissions for variant NM_000051.4(ATM):c.1051G>A (p.Asp351Asn)

gnomAD frequency: 0.00001  dbSNP: rs876659092

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000214187	SCV000275138	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-07	criteria provided, single submitter	clinical testing	The p.D351N variant (also known as c.1051G>A), located in coding exon 7 of the ATM gene, results from a G to A substitution at nucleotide position 1051. The aspartic acid at codon 351 is replaced by asparagine, an amino acid with highly similar properties. This alteration was reported in 1/13087 breast cancer cases and 0/5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). This amino acid position is highly 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	RCV000459705	SCV000546997	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 351 of the ATM protein (p.Asp351Asn). This variant is present in population databases (no rsID available, 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: 231324). 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.
GeneDx	RCV000481530	SCV000569192	uncertain significance	not provided	2024-03-12	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; Observed in individuals with breast cancer (PMID: 28779002); This variant is associated with the following publications: (PMID: 28779002)
Color Diagnostics, LLC DBA Color Health	RCV000214187	SCV000904630	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-07	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 351 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 two individuals affected with breast cancer (PMID: 28779002). This variant has been identified in 1/251144 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.
Fulgent Genetics, Fulgent Genetics	RCV002500731	SCV002814656	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2022-03-16	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000459705	SCV002090290	uncertain significance	Ataxia-telangiectasia syndrome	2021-04-29	no assertion criteria provided	clinical testing