Submissions for variant NM_000051.4(ATM):c.3016A>G (p.Met1006Val)

gnomAD frequency: 0.00005  dbSNP: rs139893395

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131127	SCV000186059	likely benign	Hereditary cancer-predisposing syndrome	2018-08-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000205686	SCV000260899	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1006 of the ATM protein (p.Met1006Val). This variant is present in population databases (rs139893395, gnomAD 0.009%). This missense change has been observed in individual(s) with personal and/or family history of cancer (PMID: 24113346, 31159747; Invitae). ClinVar contains an entry for this variant (Variation ID: 142162). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
GeneDx	RCV000585220	SCV000278818	uncertain significance	not provided	2020-04-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer (Decker 2017); This variant is associated with the following publications: (PMID: 28779002, 28652578, 24113346, 31159747)
CeGaT Center for Human Genetics Tuebingen	RCV000585220	SCV000692732	uncertain significance	not provided	2017-07-01	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000131127	SCV000821845	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131127	SCV000902981	likely benign	Hereditary cancer-predisposing syndrome	2016-04-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001328457	SCV001519598	uncertain significance	not specified	2023-01-03	criteria provided, single submitter	clinical testing	Variant summary: ATM c.3016A>G (p.Met1006Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251338 control chromosomes (gnomAD). This frequency is not higher than predicted for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4.8e-05 vs 0.004), allowing no conclusion about variant significance. c.3016A>G has been reported in the literature as a VUS in individuals undergoing multigene cancer panel testing as well as in unaffected control cohorts (example, Mauer_2014, Tsaousis_2019, Tiao_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=5) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000131127	SCV002535256	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-19	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001328457	SCV004027194	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing