Submissions for variant NM_000051.4(ATM):c.6975G>A (p.Ala2325=)

dbSNP: rs556778314

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130288	SCV000185135	likely benign	Hereditary cancer-predisposing syndrome	2019-10-11	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196388	SCV000254137	likely benign	Ataxia-telangiectasia syndrome	2024-01-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000679141	SCV000292477	uncertain significance	not provided	2024-02-23	criteria provided, single submitter	clinical testing	Located in the critical FAT domain (PMID: 23532176); Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with personal and/or family history of breast cancer, but also in unaffected controls (PMID: 35402282, 28779002, 33128190, 35264596); This variant is associated with the following publications: (PMID: 27149842, 28779002, 33128190, 35264596, 35402282, 36243179, 23532176)
Color Diagnostics, LLC DBA Color Health	RCV000130288	SCV000537558	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-17	criteria provided, single submitter	clinical testing	This synonymous variant alters the conserved G at the last nucleotide position of exon 47 of the ATM gene. Splice site prediction tools suggest this variant may have a significant impact on splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast cancer and in healthy controls (PMID: 28779002, 33128190, 35264596, 35402282). This variant has been identified in 3/251310 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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	RCV000679141	SCV001475568	uncertain significance	not provided	2019-12-27	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002243794	SCV002512252	uncertain significance	Familial cancer of breast	2021-07-13	criteria provided, single submitter	clinical testing	ACMG classification criteria: PP3 supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469019	SCV002766122	uncertain significance	not specified	2022-11-08	criteria provided, single submitter	clinical testing	Variant summary: ATM c.6975G>A (p.Ala2325Ala) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. One computational tool predicts the variant abolishes a canonical 5' splicing donor site, and three predict the variant has no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 251310 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6975G>A has been reported in the literature in individuals affected with breast cancer (Gomes_2020, Abdel-Razeq_2022, Guindalini_2022). These reports do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submitters have assessed the variant since 2014: two classified the variant as likely benign, five as uncertain significance, and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679141	SCV002774759	uncertain significance	not provided	2019-12-27	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals affected with breast cancer (PMIDs: 28779002 (2017), 33128190 (2021), 35264596 (2022), 35402282 (2022)) and unaffected controls (PMID: 28779002 (2017)). The frequency of this variant in the general population, 0.00039 (6/15234 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on ATM mRNA splicing yielded inconclusive findings . Based on the available information, we are unable to determine the clinical significance of this variant.
Mendelics	RCV000196388	SCV004176782	uncertain significance	Ataxia-telangiectasia syndrome	2023-12-29	criteria provided, single submitter	clinical testing	This ATM synonymous variant is located at a splice site, with a SpliceAI score of 0.85. In an internal analysis of 6362 Breast Cancer patients and 9128 controls, we found 15 carriers in cases and 10 in controls, yielding an odds-ratio of 2.2, p-value 0.054.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002469019	SCV005089810	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739442	SCV000805610	uncertain significance	ATM-related disorder	2024-09-06	no assertion criteria provided	clinical testing	The ATM c.6975G>A variant is not predicted to result in an amino acid change (p.=). This variant occurs at the last nucleotide of an exon and is predicted to interfere with splicing based on splicing prediction programs (SpliceAI, Jaganathan K, et al. 2019. PubMed ID: 30661751). This variant has been reported in individuals with breast cancer and/or ovarian cancer (Gomes et al. 2021. PubMed ID: 33128190; Abdel-Razeq et al. 2022. PubMed ID: 35402282) and has also been documented in controls (Supplementary Table 2 in Guindalini et al. 2022. PubMed ID: 35264596). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD, and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/141676). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.