Submissions for variant NM_000051.4(ATM):c.4091A>G (p.Asp1364Gly)

gnomAD frequency: 0.00001  dbSNP: rs751169467

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000233318	SCV000282954	uncertain significance	Ataxia-telangiectasia syndrome	2025-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1364 of the ATM protein (p.Asp1364Gly). This variant is present in population databases (rs751169467, gnomAD 0.003%). This missense change has been observed in individual(s) with a personal and/or family history suggestive of Lynch syndrome and/or breast cancer (PMID: 25186627, 25980754, 35534704, 35957908). ClinVar contains an entry for this variant (Variation ID: 236715). 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.
Eurofins Ntd Llc (ga)	RCV000295039	SCV000334766	uncertain significance	not provided	2015-09-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000575696	SCV000660497	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-07	criteria provided, single submitter	clinical testing	The p.D1364G variant (also known as c.4091A>G), located in coding exon 26 of the ATM gene, results from an A to G substitution at nucleotide position 4091. The aspartic acid at codon 1364 is replaced by glycine, an amino acid with similar properties. This alteration was detected on a 25-gene panel test in a woman who was diagnosed with breast cancer before age 50 (Tung N et al. Cancer, 2015 Jan;121:25-33). This variant was also reported in 2/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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.
Mendelics	RCV000233318	SCV000838534	uncertain significance	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000575696	SCV000903205	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-27	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 1364 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 Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25980754). This variant has been identified in 2/248572 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000233318	SCV001159914	uncertain significance	Ataxia-telangiectasia syndrome	2018-09-13	criteria provided, single submitter	clinical testing	The ATM c.4091A>G; p.Asp1364Gly variant (rs751169467), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 236715). This variant is found on two chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism. The aspartate at codon 1364 is weakly conserved but computational analyses (SIFT: damaging, PolyPhen-2: tolerated) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.Asp1364Gly variant is uncertain at this time.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001532978	SCV001748806	uncertain significance	not specified	2022-05-05	criteria provided, single submitter	clinical testing	Variant summary: ATM c.4091A>G (p.Asp1364Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 248572 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4091A>G has been reported in the literature as a VUS in settings of multigene panel testing of individuals affected with breast cancer and colorectal cancer (example, Tung_2015, Yurgelun_2015). These reports do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia or ATM-related disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV000295039	SCV001780233	uncertain significance	not provided	2023-07-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer or Lynch syndrome-associated cancer and/or polyps (Yurgelun et al., 2015; Tung et al., 2015; Guindalini et al., 2022); This variant is associated with the following publications: (PMID: 25326804, 25980754, 25186627, 35264596)
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000233318	SCV002512230	uncertain significance	Ataxia-telangiectasia syndrome	2021-10-29	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2 moderate, BP4 supporting
Sema4, Sema4	RCV000575696	SCV002528974	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-09	criteria provided, single submitter	curation
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356547	SCV001551750	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Asp1364Gly variant was identified in 1 of 2520 proband chromosomes (frequency: 0.0004) from individuals or families with Lynch syndrome (Yurgelun 2015). The variant was also identified in dbSNP (ID: rs751169467) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Invitae, Ambry Genetics and three other submitters). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 2 of 243350 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 5450 chromosomes (freq: 0.0002), Latino in 1 of 33548 chromosomes (freq: 0.00003), while the variant was not observed in the African, European, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Asp1364 residue is not 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.
Natera, Inc.	RCV000233318	SCV002079169	uncertain significance	Ataxia-telangiectasia syndrome	2020-08-19	no assertion criteria provided	clinical testing