Submissions for variant NM_000051.4(ATM):c.5369A>T (p.Asp1790Val)

dbSNP: rs746945284

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000574069	SCV000665234	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-31	criteria provided, single submitter	clinical testing	The p.D1790V variant (also known as c.5369A>T), located in coding exon 35 of the ATM gene, results from an A to T substitution at nucleotide position 5369. The aspartic acid at codon 1790 is replaced by valine, an amino acid with highly dissimilar properties. This alteration was observed with an allele frequency of 0.00057 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00053 in 11,241 female controls of Japanese ancestry. In addition, it was not observed in unselected male breast cancer patients and was observed with an allele frequency of 0.0002 in 12490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000627950	SCV000748835	uncertain significance	Ataxia-telangiectasia syndrome	2022-03-08	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 1790 of the ATM protein (p.Asp1790Val). This variant is not present in population databases (gnomAD no frequency). 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: 481089). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATM protein function. 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	RCV000574069	SCV001735163	uncertain significance	Hereditary cancer-predisposing syndrome	2020-12-03	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with valine at codon 1790 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 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003321675	SCV004027241	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000627950	SCV002081892	uncertain significance	Ataxia-telangiectasia syndrome	2020-02-28	no assertion criteria provided	clinical testing