Submissions for variant NM_000051.3(ATM):c.4365T>A (p.Ser1455Arg) (rs527471560)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165552	SCV000216284	likely benign	Hereditary cancer-predisposing syndrome	2019-01-04	criteria provided, single submitter	clinical testing	Insufficient evidence
Invitae	RCV000232578	SCV000282957	likely benign	Ataxia-telangiectasia syndrome	2020-11-21	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000165552	SCV000292206	uncertain significance	Hereditary cancer-predisposing syndrome	2020-07-28	criteria provided, single submitter	clinical testing	This missense variant replaces serine with arginine at codon 1455 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). Functional studies reported loss of kinase activity in irradiated cells and a failure to complement cell survival phenotypes in ATM-defective cells (PMID: 12969974, 29059438). This variant has been reported in individuals affected with Hodgkin lymphoma and neuroblastoma (PMID: 12969974, 29059438). This variant has been identified in 1/251188 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in control individuals (PMID: 12969974, 29059438). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780910	SCV000918552	uncertain significance	not specified	2019-08-09	criteria provided, single submitter	clinical testing	Variant summary: ATM c.4365T>A (p.Ser1455Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246182 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4365T>A has been reported in the literature in one individual affected with childhood Hodgkin disease. This report does not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. One study reported the finding of defective ATM-mediated p53 phosphorylation and Chk2 activation in lymphoblastoid cell lines obtained from a patient with childhood Hodgkin disease harboring this variant (Takagi_2004). However these results cannot be specifically correlated to the pathophysiology and in-vivo effect of this variant as the results obtained could be attributed to another genetic variant unrelated to this specific variant. The authors presented their findings in the context of possible genetic risk factors for childhood Hodgkin disease. To our knowledge, no other direct experimental evidence demonstrating an impact on protein function has been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2 VUS and 1 likely benign). Based on the evidence outlined above, the variant was classified as uncertain significance.
Cancer Genomics Group,Japanese Foundation For Cancer Research	RCV001030530	SCV001193478	uncertain significance	Hereditary breast and ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Illumina Clinical Services Laboratory,Illumina	RCV000232578	SCV001263902	uncertain significance	Ataxia-telangiectasia syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV001589033	SCV001814843	uncertain significance	not provided	2019-06-25	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 30287823, 28779002, 21910157, 12969974, 29059438)