Submissions for variant NM_000051.4(ATM):c.3919G>A (p.Gly1307Arg)

dbSNP: rs568451087

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131248	SCV000186209	likely benign	Hereditary cancer-predisposing syndrome	2019-02-22	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV000234723	SCV000282946	benign	Ataxia-telangiectasia syndrome	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001704057	SCV000729394	likely benign	not provided	2020-11-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131248	SCV000910688	benign	Hereditary cancer-predisposing syndrome	2016-10-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000234723	SCV001260528	uncertain significance	Ataxia-telangiectasia syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000608362	SCV001437333	likely benign	not specified	2020-09-14	criteria provided, single submitter	clinical testing	Variant summary: ATM c.3919G>A (p.Gly1307Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00036 in 251256 control chromosomes, predominantly at a frequency of 0.0029 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.3919G>A has been reported in the literature in individuals affected with cancer including low grade glioma and breast cancer (e.g. Shayeghi_1998, Lu_2015, Mandelker_2017) but was also reported in non-cancer controls (e.g. Pritchard_2018). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. One submitter in LOVD reports co-occurrence of the variant with 2 undefined pathogenic variants and classifies it as benign. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and one ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798449	SCV002042177	likely benign	Breast and/or ovarian cancer	2019-08-19	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225443	SCV002504706	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356054	SCV001551112	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Gly1307Arg variant was not identified in the literature nor was it identified in the GeneInsight-COGR, Cosmic, or MutDB databases. The variant was identified in dbSNP (ID: rs568451087) as "With Likely benign allele", ClinVar (classified as likely benign by Ambry Genetics, Invitae, and GeneDx), and LOVD 3.0 (1x) databases. The variant was identified in control databases in 94 of 276986 chromosomes (2 homozygous) at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). The variant was identified in the following populations: South Asian in 92 of 30782 chromosomes (freq: 0.003), Other in 1 of 6458 chromosomes (freq: 0.0002), and East Asian in 1 of 18852 chromosomes (freq: 0.0001), while the variant was not observed in the African, Latino, European, Ashkenazi Jewish, or Finnish populations. The p.Gly1307 residue is not conserved in mammals and four out of five 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 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.