Submissions for variant NM_000051.4(ATM):c.4321A>G (p.Ile1441Val)

dbSNP: rs774886013

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000582990	SCV000687540	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-15	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 1441 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 ATM-related disorders 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001036202	SCV001199553	uncertain significance	Ataxia-telangiectasia syndrome	2022-05-15	criteria provided, single submitter	clinical testing	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: 490567). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1441 of the ATM protein (p.Ile1441Val).
Ambry Genetics	RCV000582990	SCV002632109	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-22	criteria provided, single submitter	clinical testing	The p.I1441V variant (also known as c.4321A>G), located in coding exon 28 of the ATM gene, results from an A to G substitution at nucleotide position 4321. The isoleucine at codon 1441 is replaced by valine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Baylor Genetics	RCV003465301	SCV004211968	uncertain significance	Familial cancer of breast	2023-05-11	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001036202	SCV002082381	uncertain significance	Ataxia-telangiectasia syndrome	2020-12-03	no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV003151107	SCV003839203	uncertain significance	not specified	2022-05-09	no assertion criteria provided	clinical testing	DNA sequence analysis of the ATM gene demonstrated a sequence change, c.4321A>G, in exon 29 that results in an amino acid change, p.Ile1441Val. This sequence change does not appear to have been previously described in individuals with ATM-related disorders and has also not been described in population databases such as ExAC and gnomAD. The p.Ile1441Val change affects a moderately conserved amino acid residue located in a domain of the ATM protein that is known to be functional. The p.Ile1441Val substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Ile1441Val change remains unknown at this time.