Submissions for variant NM_001184.4(ATR):c.2704T>C (p.Ser902Pro)

gnomAD frequency: 0.00036  dbSNP: rs146202702

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000604475	SCV000725243	likely benign	not specified	2017-12-04	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV001058648	SCV001223234	uncertain significance	not provided	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 902 of the ATR protein (p.Ser902Pro). This variant is present in population databases (rs146202702, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ATR-related conditions. ClinVar contains an entry for this variant (Variation ID: 513755). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Illumina Laboratory Services, Illumina	RCV001147706	SCV001308547	uncertain significance	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CeGaT Center for Human Genetics Tuebingen	RCV001058648	SCV001747378	uncertain significance	not provided	2024-01-01	criteria provided, single submitter	clinical testing	ATR: PP2
Ambry Genetics	RCV002528543	SCV003533357	uncertain significance	Inborn genetic diseases	2022-06-21	criteria provided, single submitter	clinical testing	The c.2704T>C (p.S902P) alteration is located in exon 13 (coding exon 13) of the ATR gene. This alteration results from a T to C substitution at nucleotide position 2704, causing the serine (S) at amino acid position 902 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001058648	SCV001550353	uncertain significance	not provided		no assertion criteria provided	clinical testing	The ATR p.Ser902Pro variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs146202702), ClinVar (classified as likely benign by GeneDx), and LOVD 3.0. The variant was identified in control databases in 170 of 282796 at a frequency of 0.0006011 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: European (non-Finnish) in 129 of 129134 chromosomes (freq: 0.000999), Other in 7 of 7222 chromosomes (freq: 0.000969), Latino in 15 of 35436 chromosomes (freq: 0.000423), South Asian in 10 of 30610 chromosomes (freq: 0.000327), European (Finnish) in 7 of 25122 chromosomes (freq: 0.000279) and African in 2 of 24956 chromosomes (freq: 0.00008), but was not observed in the Ashkenazi Jewish or East Asian populations. The p.Ser902 residue is 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. 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001058648	SCV001743813	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001058648	SCV001964150	uncertain significance	not provided		no assertion criteria provided	clinical testing