rs199895166
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_005732.4(RAD50):c.2903G>A(p.Gly968Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000341 in 1,611,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G968R) has been classified as Uncertain significance.
Frequency
Consequence
NM_005732.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD50 | NM_005732.4 | c.2903G>A | p.Gly968Glu | missense_variant | 18/25 | ENST00000378823.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD50 | ENST00000378823.8 | c.2903G>A | p.Gly968Glu | missense_variant | 18/25 | 1 | NM_005732.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000158 AC: 24AN: 152028Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000523 AC: 13AN: 248662Hom.: 0 AF XY: 0.0000370 AC XY: 5AN XY: 134988
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1459358Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 725812
GnomAD4 genome ? AF: 0.000158 AC: 24AN: 152146Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74384
ClinVar
Submissions by phenotype
Nijmegen breakage syndrome-like disorder Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 03, 2023 | - - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 02, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 18, 2022 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 17, 2023 | The p.G968E variant (also known as c.2903G>A), located in coding exon 18 of the RAD50 gene, results from a G to A substitution at nucleotide position 2903. The glycine at codon 968 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been detected in 1/1824 patients with triple negative breast cancer who were unselected for a family history of breast or ovarian cancer (Couch FJ et al. J. Clin. Oncol., 2015 Feb;33:304-11). This alteration was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration was detected in a patient with uterine serous carcinoma (Frimer M et al. Gynecol Oncol, 2016 Apr;141:101-7). This variant was also identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 968 of the RAD50 protein (p.Gly968Glu). This variant is present in population databases (rs199895166, gnomAD 0.07%). This missense change has been observed in individual(s) with breast cancer and endometrial cancer (PMID: 25452441, 27016235). ClinVar contains an entry for this variant (Variation ID: 184957). 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 not expected to disrupt RAD50 protein function with a negative 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 13, 2023 | Variant summary: RAD50 c.2903G>A (p.Gly968Glu) 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 5.2e-05 in 248662 control chromosomes in gnomAD. This frequency is not significantly higher than estimated for a pathogenic variant in RAD50 causing Hereditary Breast And Ovarian Cancer Syndrome (5.2e-05 vs 6.3e-05), allowing no conclusion about variant significance. c.2903G>A has been reported in the literature in individuals affected with uterine serous carcinoma or Breast Cancer without strong evidence for causality (example: Couch_2015, Frimer_2016). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25452441, 27016235). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at