Submissions for variant NM_000051.4(ATM):c.2418G>T (p.Leu806Phe)

gnomAD frequency: 0.00004  dbSNP: rs587781296

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129001	SCV000172896	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-23	criteria provided, single submitter	clinical testing	The p.L806F variant (also known as c.2418G>T), located in coding exon 15 of the ATM gene, results from a G to T substitution at nucleotide position 2418. The leucine at codon 806 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration was identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers. (Pritchard AL et al. PLoS ONE, 2018 Apr;13:e0194098). This alteration has also been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J. Med. Genet., 2017 11;54:732-741). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000168332	SCV000219020	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 806 of the ATM protein (p.Leu806Phe). This variant is present in population databases (rs587781296, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 140813). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000129001	SCV000682053	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 806 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 has been reported in an individual affected with breast cancer (PMID: 28779002) and in an unaffected control individual (PMID: 29641532). This variant has been identified in 3/282616 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.
GeneDx	RCV001588979	SCV001826585	uncertain significance	not provided	2023-11-12	criteria provided, single submitter	clinical testing	Observed in individuals with breast or lung cancer (PMID: 28779002, 28843361); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28779002, 28843361)
Genetic Services Laboratory, University of Chicago	RCV001818299	SCV002066732	uncertain significance	not specified	2020-12-16	criteria provided, single submitter	clinical testing	This sequence change does not appear to have been previously described in patients with ATM-related disorders and has been described in the gnomAD database with a low population frequency of 0.0011% (dbSNP rs587781296). The p.Leu806Phe change affects a moderately conserved amino acid residue located in a domain of the ATM protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Leu806Phe substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Leu806Phe change remains unknown at this time.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149885	SCV003837635	uncertain significance	Breast and/or ovarian cancer	2021-06-09	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467100	SCV004210239	uncertain significance	Familial cancer of breast	2023-06-26	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000168332	SCV001462068	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358487	SCV001554235	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Leu806Phe variant was not identified in the literature nor was it identified in the GeneInsight-COGR, Cosmic, MutDB, or LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs587781296) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, Color Genomics). The variant was identified in control databases in 3 of 277040 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant found in European population in 3 of 126632 chromosomes (freq: 0.00002), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Leu806 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 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. This variant is classified as a variant of uncertain significance.