Submissions for variant NM_000051.4(ATM):c.5470C>T (p.Leu1824Phe)

gnomAD frequency: 0.00001  dbSNP: rs764784077

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000469808	SCV000547067	uncertain significance	Ataxia-telangiectasia syndrome	2024-02-01	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 1824 of the ATM protein (p.Leu1824Phe). This variant is present in population databases (rs764784077, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 36029002). ClinVar contains an entry for this variant (Variation ID: 407681). 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 tolerated. 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.
PreventionGenetics, part of Exact Sciences	RCV000679129	SCV000805581	uncertain significance	not provided	2017-03-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771874	SCV000904620	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-22	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 1824 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). This variant has been identified in 6/250924 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.
Ambry Genetics	RCV000771874	SCV001186123	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-21	criteria provided, single submitter	clinical testing	The p.L1824F variant (also known as c.5470C>T), located in coding exon 35 of the ATM gene, results from a C to T substitution at nucleotide position 5470. The leucine at codon 1824 is replaced by phenylalanine, an amino acid with highly similar properties. 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.
Sema4, Sema4	RCV000771874	SCV002528486	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-14	criteria provided, single submitter	curation
GeneDx	RCV000679129	SCV002559620	uncertain significance	not provided	2024-08-11	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33436325, 36029002, 28779002)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114582	SCV003800963	uncertain significance	not specified	2023-07-20	criteria provided, single submitter	clinical testing	Variant summary: ATM c.5470C>T (p.Leu1824Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 250924 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5470C>T has been reported in the literature in an individual affected with breast cancer (Decker_2017). In contrast, the variant was not found in 5560 individuals affected with prostate cancer from the PRACTICAL Consortium study groups cohort, but was in 1 of 3353 controls of European ancestry (Karlsson_2021). These reports do not provide unequivocal conclusions about association of the variant with breast or prostate cancers. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28779002, 33436325). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003470438	SCV004207079	uncertain significance	Familial cancer of breast	2024-03-11	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000469808	SCV002084184	uncertain significance	Ataxia-telangiectasia syndrome	2020-12-22	no assertion criteria provided	clinical testing