Submissions for variant NM_000051.4(ATM):c.2333A>G (p.Asn778Ser)

gnomAD frequency: 0.00001  dbSNP: rs587779820

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000589935	SCV000149062	uncertain significance	not provided	2025-02-20	criteria provided, single submitter	clinical testing	Observed in individuals with breast, ovarian, pancreatic, or other cancers (PMID: 20305132, 25479140, 26689913, 25186627, 34262154); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25479140, 26689913, 20305132, 25186627, 34262154)
Ambry Genetics	RCV000115153	SCV000185280	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	clinical testing	The p.N778S variant (also known as c.2333A>G), located in coding exon 14 of the ATM gene, results from an A to G substitution at nucleotide position 2333. The asparagine at codon 778 is replaced by serine, an amino acid with highly similar properties. This variant has been reported in several cohorts of breast cancer patients (Bernstein JL et al. J Natl Cancer Inst, 2010 Apr;102:475-83; Tung N et al. Cancer, 2015 Jan;121:25-33; Hauke J et al. Cancer Med, 2018 04;7:1349-1358) and in 1/290 individuals with pancreatic cancer (Grant RC et al. Gastroenterology, 2015 Mar;148:556-64). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195938	SCV000254068	uncertain significance	Ataxia-telangiectasia syndrome	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 778 of the ATM protein (p.Asn778Ser). This variant is present in population databases (rs587779820, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer, ovarian cancer, and/or pancreatic cancer (PMID: 20305132, 25186627, 25479140, 26689913). ClinVar contains an entry for this variant (Variation ID: 127348). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. 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.
Illumina Laboratory Services, Illumina	RCV000195938	SCV000367036	uncertain significance	Ataxia-telangiectasia syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589935	SCV000694217	uncertain significance	not provided	2017-08-21	criteria provided, single submitter	clinical testing	Variant summary: The ATM c.2333A>G (p.Asn778Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide located in the Armadillo-type fold domain (IPR016024) (InterPro). 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in the large control database ExAC in 1/121360 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). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. This variant was reported in patients with breast, ovarian, and pancreatic cancer without strong evidence for causality (Bernstein_2010, Grant_2015, Lu_2015, Tung_2015). The variant of interest has not, to our knowledge, been reported in affected individuals via reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. This variant is classified as a variant of uncertain significance (VUS) until more clinical and functional studies become available.
Color Diagnostics, LLC DBA Color Health	RCV000115153	SCV000911181	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-17	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 778 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 observed in individuals affected with breast, pancreatic and ovarian cancers (PMID: 20305132, 25186627, 25479140, 26689913, 29522266). This variant has been identified in 3/251370 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.
Athena Diagnostics	RCV000589935	SCV002771673	uncertain significance	not provided	2022-06-24	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000589935	SCV003916779	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	ATM: BP1, BP4
Natera, Inc.	RCV000195938	SCV002079684	uncertain significance	Ataxia-telangiectasia syndrome	2020-07-05	no assertion criteria provided	clinical testing