ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5630T>C (p.Phe1877Ser) (rs202028401)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159735 SCV000209749 uncertain significance not provided 2019-10-01 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with non-Hodgkin lymphoma (Sipahimalani 2007); This variant is associated with the following publications: (PMID: 17640065)
Invitae RCV000472045 SCV000547090 likely benign Ataxia-telangiectasia syndrome 2020-09-09 criteria provided, single submitter clinical testing
Ambry Genetics RCV000567744 SCV000667915 likely benign Hereditary cancer-predisposing syndrome 2019-01-17 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Color Health, Inc RCV000567744 SCV000913965 uncertain significance Hereditary cancer-predisposing syndrome 2020-11-23 criteria provided, single submitter clinical testing This missense variant replaces phenylalanine with serine at codon 1877 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant not been reported in an individual affected with non-Hodgkin lymphoma (PMID: 17640065). This variant has been identified in 11/249188 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357645 SCV001553172 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Phe1877Ser variant was not identified in the literature nor was it identified in the following databases: COGR, Cosmic, MutDB, or LOVD 3.0. The variant was identified in dbSNP (ID: rs202028401) “With Uncertain significance allele”, ClinVar (classified uncertain significance by GeneDx and Invitae), Clinvitae (2x), and in control databases in 11 of 244076 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: European Non-Finnish in 1 of 110796 chromosomes (freq: 0.000009), and South Asian in 10 of 30752 chromosomes (freq: 0.0003); it was not observed in the African, “Other”, Latino, Ashkenazi Jewish, East Asian, European Finnish populations. The p.Phe1877Ser 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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.

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