ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2338A>T (p.Met780Leu) (rs587781446)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129362 SCV000184126 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-24 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000560137 SCV000622322 uncertain significance Ataxia-telangiectasia syndrome 2019-06-01 criteria provided, single submitter clinical testing This sequence change replaces methionine with leucine at codon 780 of the ATM protein (p.Met780Leu). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and leucine. This variant is present in population databases (rs587781446, ExAC 0.01%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 141031). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000129362 SCV000687374 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-07 criteria provided, single submitter clinical testing
Pittsburgh Clinical Genomics Laboratory,University of Pittsburgh Medical Center RCV001249848 SCV001424010 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence variant is a single nucleotide substitution (A>T) that results in a methionine to leucine amino acid change at residue 780 in the ATM protein. This is a rare variant that has been reported at a frequency of 0.000004 (1/251360 alleles) in the gnomAD v2.1 population database. The variant is not located in any known ATM functional domain, and multiple bioinformatic tools queried predict that this variant will have a neutral effect on protein function; however, these predictions have not been confirmed by functional studies, to our knowledge. Additionally, we could find no report of this variant in research or case studies. Methionine at this position is not highly conserved in mammals. At the current time, there is insufficient information to determine if this variant is benign or pathogenic; we consider it to be a variant of uncertain significance.

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