ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1960C>A (p.Gln654Lys) (rs528165789)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122828 SCV000166085 uncertain significance Ataxia-telangiectasia syndrome 2020-10-30 criteria provided, single submitter clinical testing This sequence change replaces glutamine with lysine at codon 654 of the ATM protein (p.Gln654Lys). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and lysine. This variant is present in population databases (rs528165789, ExAC 0.01%). This variant has been reported in individuals affected with breast cancer (PMID: 12362033, 19781682, 26976419), colorectal cancer (PMID: 28135145) and unspecified cancer (PMID: 24416720). ClinVar contains an entry for this variant (Variation ID: 135739). 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.
Ambry Genetics RCV000165083 SCV000215786 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-29 criteria provided, single submitter clinical testing The p.Q654K variant (also known as c.1960C>A), located in coding exon 12 of the ATM gene, results from a C to A substitution at nucleotide position 1960. The glutamine at codon 654 is replaced by lysine, an amino acid with similar properties. This alteration has been detected in 1/4112 breast cancer patients and 0/2399 healthy control individuals across numerous studies (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85:427-46). 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.
GeneDx RCV000254742 SCV000322091 uncertain significance not provided 2021-01-21 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer, colon cancer, and cancer of unknown primary (Maillet 2002, Tavtigian 2009, Petereit 2013, Tung 2016, Yurgelun 2017); This variant is associated with the following publications: (PMID: 28135145, 28652578, 19781682, 12362033, 24416720, 26976419, 28779002, 28717660)
Color Health, Inc RCV000165083 SCV000902998 likely benign Hereditary cancer-predisposing syndrome 2017-01-30 criteria provided, single submitter clinical testing
Natera, Inc. RCV000122828 SCV001461087 uncertain significance Ataxia-telangiectasia syndrome 2020-01-08 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354480 SCV001549108 uncertain significance Familial pancreatic carcinoma no assertion criteria provided clinical testing The ATM p.Gln654Lys variant was identified in 4 of 3680 proband chromosomes (frequency: 0.001) from individuals or families with breast or colon cancer and was not identified in 280 control chromosomes from healthy individuals (Maillet 2002, Petereit 2013, Tung 2016, Yurgelun 2017). The variant was also identified in dbSNP (ID: rs528165789) as "With Pathogenic, Uncertain significance allele", and in ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, and GeneDx). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 7 of 246108 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 5 of 111600 chromosomes (freq: 0.00005), and South Asian in 2 of 30782 chromosomes (freq: 0.00007); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Gln654 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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