Submissions for variant NM_000051.4(ATM):c.8015A>C (p.Asp2672Ala)

dbSNP: rs763161651

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219117	SCV000275400	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-26	criteria provided, single submitter	clinical testing	The p.D2672A variant (also known as c.8015A>C), located in coding exon 54 of the ATM gene, results from an A to C substitution at nucleotide position 8015. The aspartic acid at codon 2672 is replaced by alanine, an amino acid with dissimilar properties. This variant was identified in a patient with breast cancer as part of a large Canadian cohort study of 2870 individuals (Bhai P et al. Front Genet, 2021 Jul;12:698595). This alteration was also detected in multiple high risk breast and ovarian cancer patients (Decker B et al. J Med Genet, 2017 11;54:732-741; Hauke J et al. Cancer Med, 2018 04;7:1349-1358; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). In one study, this alteration was not identified in 516 chronic lymphocytic leukemia patients of European descent but detected in 1/8920 ethnically matched normal controls (Tiao G et al. Leukemia, 2017 10;31:2244-2247). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000479711	SCV000567216	uncertain significance	not provided	2021-03-01	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in a BRCA1/2-negative individual with breast cancer (Hauke 2018); This variant is associated with the following publications: (PMID: 29522266)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000551886	SCV000622795	uncertain significance	Ataxia-telangiectasia syndrome	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 2672 of the ATM protein (p.Asp2672Ala). This variant is present in population databases (rs763161651, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 231524). 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 disruptive. 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.
Color Diagnostics, LLC DBA Color Health	RCV000219117	SCV000682451	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-29	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with alanine at codon 2672 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 29522266, 33471991; Color Health internal data). This variant has been identified in 1/251206 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.
Baylor Genetics	RCV003469035	SCV004210314	uncertain significance	Familial cancer of breast	2023-06-02	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003491978	SCV004239516	uncertain significance	Breast and/or ovarian cancer	2022-09-12	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355903	SCV001550921	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Asp2672Ala variant was not identified in the literature nor was it identified in the GeneInsight-COGR, Cosmic, MutDB, LOVD 3.0, databases. The variant was identified in dbSNP (ID: rs763161651) as “With Uncertain significance allele”, in ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Invitae, Color Genomics), and in Clinvitae databases. The variant was identified in control databases in 1 of 245980 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 1 of 111484 chromosomes (freq: 0.00001), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Asp2672 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.