Submissions for variant NM_000051.4(ATM):c.4784A>G (p.Asn1595Ser)

dbSNP: rs777812804

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231590	SCV000282968	likely benign	Ataxia-telangiectasia syndrome	2025-01-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000575403	SCV000665200	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-27	criteria provided, single submitter	clinical testing	The p.N1595S variant (also known as c.4784A>G), located in coding exon 31 of the ATM gene, results from an A to G substitution at nucleotide position 4784. The asparagine at codon 1595 is replaced by serine, an amino acid with highly similar properties. This alteration has been reported as a variant of uncertain significance in 1/1197 individuals from Greece, Romania, and Turkey undergoing multigene panel testing for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer 2019 Jun;19(1):535). This alteration was also identified in 1/2105 women with invasive breast cancer who were tested for variants in the ATM gene (Bernstein JL et al. J Natl Cancer Inst 2010 Apr;102(7):475-83). This amino acid position is not well 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	RCV000575403	SCV000682222	uncertain significance	Hereditary cancer-predisposing syndrome	2019-02-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586254	SCV000694292	uncertain significance	not provided	2016-09-26	criteria provided, single submitter	clinical testing	Variant summary: The ATM c.4784A>G (p.Asn1595Ser) variant involves the alteration of a conserved nucleotide and results in a replacement of a medium size and polar Asparagine (N) with a small size and polar Serine (S) located outside of known functional domains (InterPro, Pfam). 3/3 in silico tools predict a benign outcome for this substitution (SNPs&GO and Mutation taster not captured due to low reliability index). This variant was found in 1/121324 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). To our knowledge, the variant has not been reported in affected patients with strong evidence for causality and studies assessing the impact the variant may have on the function of ATM protein have not been published at the time of classification either. One clinical diagnostic laboratory classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
GeneKor MSA	RCV000575403	SCV000821857	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000586254	SCV003930484	uncertain significance	not provided	2023-05-24	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 an individual with contralateral breast cancer and absent in controls (Bernstein et al., 2010); This variant is associated with the following publications: (PMID: 31159747, 20305132)
Baylor Genetics	RCV003469126	SCV004212195	uncertain significance	Familial cancer of breast	2024-03-13	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000231590	SCV002075320	uncertain significance	Ataxia-telangiectasia syndrome	2021-01-28	no assertion criteria provided	clinical testing