ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1880T>G (p.Phe627Cys) (rs546087885)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000213749 SCV000277199 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-18 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Insufficient evidence
Invitae RCV000456562 SCV000547114 uncertain significance Ataxia-telangiectasia syndrome 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with cysteine at codon 627 of the ATM protein (p.Phe627Cys). The phenylalanine residue is moderately conserved and there is a large physicochemical difference between phenylalanine and cysteine. This variant is present in population databases (rs546087885, ExAC 0.003%). This variant has been reported in the literature in individuals with breast cancer (PMID: 11996792, 19781682, 12935922). ClinVar contains an entry for this variant (Variation ID: 232928). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). In summary, this variant has uncertain impact on ATM function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000482413 SCV000567772 uncertain significance not provided 2017-08-15 criteria provided, single submitter clinical testing This variant is denoted ATM c.1880T>G at the cDNA level, p.Phe627Cys (F627C) at the protein level, and results in the change of a Phenylalanine to a Cysteine (TTC>TGC). This variant has been observed in at least one breast cancer case (Sommer 2002, Tavtigian 2009). ATM Phe627Cys was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Phenylalanine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Phe627Cys occurs at a position where amino acids with properties similar to Phenylalanine are tolerated across species and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether ATM Phe627Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000213749 SCV000682010 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-02 criteria provided, single submitter clinical testing
Counsyl RCV000456562 SCV000794565 uncertain significance Ataxia-telangiectasia syndrome 2017-10-02 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000482413 SCV000805509 uncertain significance not provided 2017-08-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193666 SCV001362660 uncertain significance not specified 2019-10-24 criteria provided, single submitter clinical testing Variant summary: ATM c.1880T>G (p.Phe627Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250808 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1880T>G has been reported in the literature in individuals affected with Breast Cancer (Bernstein_2010, Sommer_2003, Tavtigian_2009). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GenomeConnect, ClinGen RCV000482413 SCV001423473 not provided not provided no assertion provided phenotyping only Variant interpretted as Uncertain significance and reported on 12-16-2019 by Lab or GTR ID Credit Valley Hospital Department of Laboratory Medicine. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.