Submissions for variant NM_000051.4(ATM):c.5323T>G (p.Leu1775Val)

gnomAD frequency: 0.00001  dbSNP: rs768820804

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000548528	SCV000622580	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1775 of the ATM protein (p.Leu1775Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 453573). 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.
Ambry Genetics	RCV000573724	SCV000660614	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-12	criteria provided, single submitter	clinical testing	The p.L1775V variant (also known as c.5323T>G), located in coding exon 35 of the ATM gene, results from a T to G substitution at nucleotide position 5323. The leucine at codon 1775 is replaced by valine, an amino acid with highly similar properties. This alteration has 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, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000573724	SCV001733545	uncertain significance	Hereditary cancer-predisposing syndrome	2020-08-03	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 1775 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 two individuals affected with breast cancer (PMID: 28779002). This variant has not been identified 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	RCV002060287	SCV002496248	uncertain significance	not provided	2023-03-30	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer and absent in controls (Decker et al., 2017); This variant is associated with the following publications: (PMID: 24705254, 28779002)
Baylor Genetics	RCV004568679	SCV005057013	uncertain significance	Familial cancer of breast	2024-02-06	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000548528	SCV002081837	uncertain significance	Ataxia-telangiectasia syndrome	2020-07-20	no assertion criteria provided	clinical testing