Submissions for variant NM_000051.4(ATM):c.4703A>G (p.His1568Arg)

gnomAD frequency: 0.00001  dbSNP: rs368830730

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131606	SCV000186622	likely benign	Hereditary cancer-predisposing syndrome	2021-08-04	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167871	SCV000218517	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 1568 of the ATM protein (p.His1568Arg). This variant is present in population databases (rs368830730, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of ATM-related conditions (PMID: 30995915, 31159747). ClinVar contains an entry for this variant (Variation ID: 142472). 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 arginine 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	RCV000480209	SCV000566386	uncertain significance	not provided	2022-04-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with personal and/or family histories of cancer and in unaffected controls (Momozawa 2018, Tsaousis 2019, Germani 2020); This variant is associated with the following publications: (PMID: 27720647, 30995915, 31159747, 32957588, 30287823)
GeneKor MSA	RCV000131606	SCV000821855	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131606	SCV000902861	likely benign	Hereditary cancer-predisposing syndrome	2017-01-25	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798455	SCV002042231	uncertain significance	Breast and/or ovarian cancer	2020-05-26	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000167871	SCV001462337	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355688	SCV001550643	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.His1568Arg variant was identified in 1 of 40,106 proband chromosomes (frequency: 0.00003) from individuals with unspecified hereditary cancer and was present in 1 of 24,980 control chromosomes (frequency: 0.00004) from healthy individuals (Momozawa 2018, Mu 2016). The variant was identified in dbSNP (rs368830730) as “with uncertain significance allele”, ClinVar (classified as uncertain significance by GeneDx, Invitae, Ambry Genetics and GeneKor; and as likely benign by Color) and LOVD 3.0 (observed 1x). The variant was identified in control databases in 10 of 245,814 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 10 of 111,368 chromosomes (freq: 0.00009), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.His1568 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.