ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7988T>C (p.Val2663Ala) (rs377648506)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656763 SCV000209650 uncertain significance not provided 2018-10-17 criteria provided, single submitter clinical testing This variant is denoted ATM c.7988T>C at the cDNA level, p.Val2663Ala (V2663A) at the protein level, and results in the change of a Valine to an Alanine (GTT>GCT). This variant has been observed in at least one individual with breast cancer and another with thyroid cancer (Tung 2016, Yehia 2018). Additionally, ATM Val2663Ala was identified in 1/46 healthy African-European individuals undergoing whole exome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. ATM Val2663Ala was observed at an allele frequency of 0.05% (12/24028) in individuals of African ancestry in large population cohorts (Lek 2016). ATM Val2663Ala is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Val2663Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000214426 SCV000278121 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-26 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). 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 2020-12-04 criteria provided, single submitter clinical testing
Color Health, Inc 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 2020-11-24 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
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

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