ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3175G>A (p.Ala1059Thr) (rs370282831)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000211995 SCV000149081 uncertain significance not provided 2018-03-29 criteria provided, single submitter clinical testing This variant is denoted ATM c.3175G>A at the cDNA level, p.Ala1059Thr (A1059T) at the protein level, and results in the change of an Alanine to a Threonine (GCC>ACC). This variant was not observed in any of 13,087 breast cancer cases, but was identified in 1/5,488 unaffected controls (Decker 2017). This variant has also been observed in at least one individual with Lynch syndrome-associated cancer and/or polyps (Yurgelun 2015). ATM Ala1059Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the beta-adaptin interaction domain (Tavtigian 2009). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Ala1059Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115172 SCV000185778 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-29 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Ambry Genetics RCV000190775 SCV000244216 uncertain significance Inborn genetic diseases criteria provided, single submitter clinical testing UNCERTAIN: Alteration of Uncertain Clinical Significance Detected
Invitae RCV000465718 SCV000546972 likely benign Ataxia-telangiectasia syndrome 2019-12-03 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515253 SCV000611356 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
Color RCV000115172 SCV000687457 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-19 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779787 SCV000916585 uncertain significance not specified 2018-08-03 criteria provided, single submitter clinical testing Variant summary: ATM c.3175G>A (p.Ala1059Thr) results in a non-conservative amino acid change located in the outside of any known domain of 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 1.1e-05 in 277044 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3175G>A has been reported in the literature in individuals affected with BrC, LS, CLL. These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia or Brest 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. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Pittsburgh Clinical Genomics Laboratory,University of Pittsburgh Medical Center RCV001249849 SCV001424011 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-05-14 criteria provided, single submitter clinical testing This sequence variant is a single nucleotide substitution (G>A) that results in an alanine to threonine amino acid change at residue 1059 in the ATM protein. This is a previously reported, rare variant in a control population dataset (gnomAD database, 3/277,044 alleles, 0.0011% overall frequency) that has been observed in at least one individual with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). The Ala1059 residue is not located within a domain typically recognized as critical for ATM function in the DNA mismatch repair pathway. Bioinformatic tools queried are in disagreement with whether this alanine to threonine amino acid substitution would be damaging. The alanine residue at this position is only moderately evolutionarily conserved across mammalian species examined. All six ClinVar entries for this variant report the significance of this variant to be uncertain. Based upon the evidence, we also consider this to be a variant of uncertain significance.

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