Submissions for variant NM_000051.4(ATM):c.5630T>C (p.Phe1877Ser)

gnomAD frequency: 0.00001  dbSNP: rs202028401

Total submissions: 7

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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000472045	SCV000547090	likely benign	Ataxia-telangiectasia syndrome	2023-12-30	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	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.
Color Diagnostics, LLC DBA Color Health	RCV000567744	SCV000913965	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-24	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. In a large international case-control meta-analysis, this variant was reported in 2/60466 breast cancer cases and 1/53461 controls (PMID: 33471991). This variant has also 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000159735	SCV002010805	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV003338433	SCV004047787	uncertain significance	Familial cancer of breast		criteria provided, single submitter	clinical testing	The missense c.5630T>C (p.Phe1877Ser) variant in ATM gene has been submitted to ClinVar as a Variant of Uncertain Significance, but no details are available for independent assessment. It has not been reported in affected individuals. The p.Val151Met variant is observed in 0.004% alleles in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The amino acid Phe at position 1877 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Phe1877Ser in ATM is predicted as conserved by PhyloP across 100 vertebrates. For these reasons, this variant has been classified as 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.