Submissions for variant NM_000051.4(ATM):c.7988T>C (p.Val2663Ala)

gnomAD frequency: 0.00010  dbSNP: rs377648506

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656763	SCV000209650	uncertain significance	not provided	2023-06-14	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history with breast and other cancers (Tung et al., 2016; Yehia et al., 2018; Matejcic et al., 2020); This variant is associated with the following publications: (PMID: 29684080, 24728327, 26976419, 30171174, 26193622, 32832836)
Ambry Genetics	RCV000214426	SCV000278121	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-03	criteria provided, single submitter	clinical testing	The p.V2663A variant (also known as c.7988T>C), located in coding exon 53 of the ATM gene, results from a T to C substitution at nucleotide position 7988. The valine at codon 2663 is replaced by alanine, an amino acid with similar properties. This alteration has been reported in a cohort of 488 patients with stages I to III breast cancer who were tested with a 25-gene panel test (Tung N et al. J. Clin. Oncol., 2016 May;34:1460-8). In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This variant was identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This amino acid position is 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.
Invitae	RCV000231221	SCV000283068	likely benign	Ataxia-telangiectasia syndrome	2024-01-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000214426	SCV000911033	likely benign	Hereditary cancer-predisposing syndrome	2016-09-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120160	SCV000916554	uncertain significance	not specified	2023-09-07	criteria provided, single submitter	clinical testing	Variant summary: ATM c.7988T>C (p.Val2663Ala) 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 5.6e-05 in 251198 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia Telangiectasia or Breast Cancer, allowing no conclusion about variant significance. c.7988T>C has been reported in the literature in at-least one individual affected with Breast Cancer (Tung_2016). This report does not provide unequivocal conclusions about association of the variant with Ataxia Telangiectasia or Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 26976419). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=4; Likely benign, n=3; Benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225366	SCV002504772	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000231221	SCV003827474	uncertain significance	Ataxia-telangiectasia syndrome	2020-03-12	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315730	SCV004019737	likely benign	Familial cancer of breast	2023-04-03	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
PreventionGenetics, part of Exact Sciences	RCV003415906	SCV004118471	uncertain significance	ATM-related condition	2023-09-29	criteria provided, single submitter	clinical testing	The ATM c.7988T>C variant is predicted to result in the amino acid substitution p.Val2663Ala. This variant has been reported individuals with breast cancer (Table A2, Tung et al. 2016. PubMed ID: 26976419; Table S2, Wilson et al. 2019. PubMed ID: 30171174), unspecified cancer types (Table S9, Yehia et al. 2018. PubMed ID: 29684080), and inflammatory bowel disease (Table S2, Kelsen et al. 2015. PubMed ID: 26193622). This variant is reported in 0.052% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108204673-T-C) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/133635/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
ITMI	RCV000120160	SCV000084302	not provided	not specified	2013-09-19	no assertion provided	reference population
Natera, Inc.	RCV000231221	SCV001462597	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing