Submissions for variant NM_000051.4(ATM):c.928A>G (p.Ser310Gly)

dbSNP: rs745773225

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167964	SCV000218612	likely benign	Ataxia-telangiectasia syndrome	2024-01-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000219840	SCV000273551	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-03	criteria provided, single submitter	clinical testing	The p.S310G variant (also known as c.928A>G), located in coding exon 7 of the ATM gene, results from an A to G substitution at nucleotide position 928. The serine at codon 310 is replaced by glycine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000481289	SCV000569907	uncertain significance	not provided	2022-07-17	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; Has not been previously published as pathogenic or benign to our knowledge
Color Diagnostics, LLC DBA Color Health	RCV000219840	SCV000687882	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-04	criteria provided, single submitter	clinical testing	This missense variant replaces serine with glycine at codon 310 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. In a large international case-control meta-analysis, this variant was reported in 1/60465 breast cancer cases and 1/53460 controls (PMID: 33471991). This variant has been identified in 4/250870 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Neuberg Centre For Genomic Medicine, NCGM	RCV003338436	SCV004047091	uncertain significance	Familial cancer of breast		criteria provided, single submitter	clinical testing	The missense variant c.928A>G (p.Ser310Gly) in ATM gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant has been reported to the ClinVar database as Uncertain Significance. The p.Ser310Gly variant is novel (not in any individuals) in 1000 Genomes. The amino acid Ser at position 310 is changed to a Gly changing protein sequence and it might alter its composition and physico-chemical properties. The residue is conserved across species. The amino acid change p.Ser310Gly in ATM is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significant.
Baylor Genetics	RCV003338436	SCV005056923	uncertain significance	Familial cancer of breast	2024-03-03	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000167964	SCV001456871	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000481289	SCV001549215	uncertain significance	not provided		no assertion criteria provided	clinical testing	The ATM p.Ser310Gly variant was not identified in the literature nor was it identified in the COGR, Cosmic, MutDB, or LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs745773225) as “With Uncertain significance allele”, and in ClinVar (4x as uncertain significance by Invitae, Ambry Genetics, GeneDx, Color Genomics). The variant was identified in control databases in 4 of 245900 chromosomes at a frequency of 0.000016 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the South Asian population in 4 of 30778 chromosomes (freq: 0.00013). It was not observed in the African, “Other”, Latino, European Non-Finnish, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Ser310 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 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this 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.