ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.3420G>A (p.Met1140Ile)

gnomAD frequency: 0.00004  dbSNP: rs748377319
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000549375 SCV000628265 uncertain significance Hereditary cancer-predisposing syndrome 2023-12-02 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1140 of the RAD50 protein (p.Met1140Ile). This variant is present in population databases (rs748377319, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with RAD50-related conditions. ClinVar contains an entry for this variant (Variation ID: 457449). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RAD50 protein function with a positive predictive value of 80%. 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 RCV000549375 SCV000663643 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-15 criteria provided, single submitter clinical testing The p.M1140I variant (also known as c.3420G>A), located in coding exon 22 of the RAD50 gene, results from a G to A substitution at nucleotide position 3420. The methionine at codon 1140 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
KCCC/NGS Laboratory, Kuwait Cancer Control Center RCV003314607 SCV004013447 uncertain significance Familial cancer of breast 2023-07-18 criteria provided, single submitter clinical testing This sequence change replaces Methionine with isoleucine at codon 1140 of the RAD50 protein (p.Met1140Ile). This amino acid position is highly conserved (PhyloP=9.48) .This variant is present in population databases (rs748377319, gnomAD 0.03%). ClinVar contains an entry for this variant (Variation ID: 457449) by two diagnostic lab both classify this variant as uncertain significance . Functional study not available for this variant .In-silico predictions show pathogenic computational verdict (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging") 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003987585 SCV004804274 uncertain significance not specified 2024-01-08 criteria provided, single submitter clinical testing

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