ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5693G>A (p.Arg1898Gln) (rs370680798)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000120146 SCV000209752 likely benign not specified 2017-09-18 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.
Ambry Genetics RCV000159738 SCV000214670 likely benign Hereditary cancer-predisposing syndrome 2018-07-31 criteria provided, single submitter clinical testing In silico models in agreement (benign) ;Other data supporting benign classification;Subpopulation frequency in support of benign classification
Invitae RCV000550304 SCV000622617 benign Ataxia-telangiectasia syndrome 2020-12-03 criteria provided, single submitter clinical testing
Color Health, Inc RCV000159738 SCV000910886 benign Hereditary cancer-predisposing syndrome 2016-12-07 criteria provided, single submitter clinical testing
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.

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