Submissions for variant NM_000051.4(ATM):c.5693G>A (p.Arg1898Gln)

gnomAD frequency: 0.00001  dbSNP: rs370680798

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001719879	SCV000209752	likely benign	not provided	2018-05-25	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24728327, 26976419, 25480502)
Ambry Genetics	RCV000159738	SCV000214670	likely benign	Hereditary cancer-predisposing syndrome	2018-07-31	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	RCV000550304	SCV000622617	benign	Ataxia-telangiectasia syndrome	2024-01-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000159738	SCV000910886	benign	Hereditary cancer-predisposing syndrome	2016-12-07	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149822	SCV003837811	likely benign	Breast and/or ovarian cancer	2021-09-21	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120146	SCV004027246	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001719879	SCV004133260	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	ATM: BP4, BS2
Breakthrough Genomics, Breakthrough Genomics	RCV001719879	SCV005218458	likely benign	not provided		criteria provided, single submitter	not provided
ITMI	RCV000120146	SCV000084287	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355719	SCV001550676	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	ATM, EXON38, c.5693G>A, p.Arg1898Gln, Heterozygous, Likely BenignrnThe ATM p.Arg1898Gln variant was identified in 2 of 7928 proband chromosomes (frequency: 0.0003) from individuals with breast or thyroid cancer and was present in 1 of 1362 control chromosomes (frequency: 0.0007) from healthy individuals (Tung 2016, Yehia 2018, Bodian 2014). The variant was identified in dbSNP as “with likely benign allele” and in ClinVar (classified as likely benign by Invitae and 2 other submitters; and as benign by Color). The variant was identified in control databases in 80 of 245,810 chromosomes (2 homozygous) at a frequency of 0.0003, 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: South Asian in 68 of 30772 chromosomes (freq: 0.002), Latino in 3 of 33,538 chromosomes (freq: 0.00009) and European in 9 of 111,452 chromosomes (freq: 0.00008), but not in the African, Other, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Arg1898 residue is conserved in mammals but not in more distantly related organisms, although computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV004551179	SCV004772508	likely benign	ATM-related disorder	2020-11-20	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).