ClinVar Miner

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

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Total submissions: 6
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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 2017-10-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000231221 SCV000283068 uncertain significance Ataxia-telangiectasia syndrome 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 2663 of the ATM protein (p.Val2663Ala). The valine residue is moderately conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs377648506, ExAC 0.05%). This variant has been reported in an individual affected with breast cancer (PMID: 26976419). ClinVar contains an entry for this variant (Variation ID: 133635). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000214426 SCV000911033 likely benign Hereditary cancer-predisposing syndrome 2016-09-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000120160 SCV000916554 uncertain significance not specified 2018-03-12 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 5.4e-05 in 276988 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (5.4e-05 vs 4.00e-03), allowing no conclusion about variant significance. c.7988T>C has been reported in the literature in one individual affected with breast cancer (Tung_2016). This report does not provide unequivocal conclusions about association of the variant with HBOC. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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.
ITMI RCV000120160 SCV000084302 not provided not specified 2013-09-19 no assertion provided reference population

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