ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.6827T>G (p.Phe2276Cys)

dbSNP: rs753389616
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV000581015 SCV000682367 uncertain significance Hereditary cancer-predisposing syndrome 2023-12-05 criteria provided, single submitter clinical testing This missense variant replaces phenylalanine with cysteine at codon 2276 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with ATM-related disorders in the literature. This variant has been identified in 1/251160 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001036993 SCV001200384 uncertain significance Ataxia-telangiectasia syndrome 2021-08-20 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with cysteine at codon 2276 of the ATM protein (p.Phe2276Cys). The phenylalanine residue is moderately conserved and there is a large physicochemical difference between phenylalanine and cysteine. This variant is present in population databases (rs753389616, ExAC 0.006%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 489581). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C25"). 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 RCV000581015 SCV002664743 uncertain significance Hereditary cancer-predisposing syndrome 2022-03-07 criteria provided, single submitter clinical testing The p.F2276C variant (also known as c.6827T>G), located in coding exon 46 of the ATM gene, results from a T to G substitution at nucleotide position 6827. The phenylalanine at codon 2276 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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