Submissions for variant NM_001184.4(ATR):c.2290A>G (p.Lys764Glu)

gnomAD frequency: 0.00340  dbSNP: rs77208665

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000145296	SCV000192373	uncertain significance	Seckel syndrome 1	2013-11-14	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000223960	SCV000281656	likely benign	not provided	2016-01-20	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000223960	SCV001001187	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000223960	SCV001154078	likely benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	ATR: BP4, BS2
Illumina Laboratory Services, Illumina	RCV000145296	SCV001312159	benign	Seckel syndrome 1	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
GeneDx	RCV000223960	SCV001855313	benign	not provided	2019-10-14	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28787443)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000223960	SCV001550705	uncertain significance	not provided		no assertion criteria provided	clinical testing	The ATR p.Lys764Glu variant was identified in 1 of 100 proband chromosomes (frequency: 0.01) from individuals or families with breast cancer and was not identified in 72 control chromosomes from healthy individuals (Durocher_2006_17010193). In Wang et al., the variant was also identified in 1/48 breast cancer tumours (Wang_2008_PMID: 18281469). The variant was also identified in the following databases: dbSNP (ID: rs77208665) and was found in ClinVar (where it was reported as likely benign and a VUS for Seckel syndrome 1), Clinvitae, Cosmic (with a FATHMM prediction of Pathogenic (score=0.95)), MutDB and LOVD 3.0. The variant was identified in control databases in 902 of 281492 chromosomes (5 homozygous) at a frequency of 0.003204 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 64 of 10326 chromosomes (freq: 0.006198), European (non-Finnish) in 630 of 128766 chromosomes (freq: 0.004893), other in 26 of 7180 chromosomes (freq: 0.003621), Latino in 89 of 35200 chromosomes (freq: 0.002528), European (Finnish) in 53 of 25088 chromosomes (freq: 0.002113), South Asian in 26 of 30084 chromosomes (freq: 0.000864) and African in 14 of 24956 chromosomes (freq: 0.000561); it was not observed in the East Asian populations. The p.Lys764 residue is not highly conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. 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.