rs377260382
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PS1_ModeratePP5_Very_Strong
The NM_005732.4(RAD50):c.3G>A(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000113 in 1,614,054 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00012 ( 1 hom. )
Consequence
RAD50
NM_005732.4 start_lost
NM_005732.4 start_lost
Scores
6
5
5
Clinical Significance
Conservation
PhyloP100: 9.76
Genes affected
RAD50 (HGNC:9816): (RAD50 double strand break repair protein) The protein encoded by this gene is highly similar to Saccharomyces cerevisiae Rad50, a protein involved in DNA double-strand break repair. This protein forms a complex with MRE11 and NBS1. The protein complex binds to DNA and displays numerous enzymatic activities that are required for nonhomologous joining of DNA ends. This protein, cooperating with its partners, is important for DNA double-strand break repair, cell cycle checkpoint activation, telomere maintenance, and meiotic recombination. Knockout studies of the mouse homolog suggest this gene is essential for cell growth and viability. Mutations in this gene are the cause of Nijmegen breakage syndrome-like disorder.[provided by RefSeq, Apr 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_005732.4 (RAD50) was described as [Likely_pathogenic] in ClinVar as 229813
PP5
Variant 5-132557327-G-A is Pathogenic according to our data. Variant chr5-132557327-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 128024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD50 | NM_005732.4 | c.3G>A | p.Met1? | start_lost | 1/25 | ENST00000378823.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD50 | ENST00000378823.8 | c.3G>A | p.Met1? | start_lost | 1/25 | 1 | NM_005732.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152244Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000477 AC: 12AN: 251490Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135922
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GnomAD4 exome AF: 0.000120 AC: 176AN: 1461810Hom.: 1 Cov.: 34 AF XY: 0.000110 AC XY: 80AN XY: 727210
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GnomAD4 genome AF: 0.0000394 AC: 6AN: 152244Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74382
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 24, 2024 | The p.M1? variant (also known as c.3G>A) is located in coding exon 1 of the RAD50 gene and results from a G to A substitution at nucleotide position 3. This alters the methionine residue at the initiation codon (ATG). However, the RAD50 gene contains a second in-frame methionine 21 nucleotides (seven amino acids) downstream of the canonical start site. This has the potential to function as an alternate translation initiation site, resulting in the removal of the first six amino acids from the protein; however, direct evidence is unavailable. This alteration was detected in 1/104 Irish familial breast cancer families and in 0/140 controls (Aloraifi F et al. FEBS J. 2015 Sep;282:3424-37). This alteration has also been reported in conjunction with a BRCA2 mutation in an individual diagnosed with breast cancer at age 49 (Foley SB et al. EBioMedicine. 2015 Jan;2:74-81) and an individual with pancreatic cancer at age 72 who had a first degree relative with pancreatic cancer (Slavin TP et al. Fam. Cancer 2018 04;17(2):235-245). This amino acid position is highly conserved in available vertebrate species. In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 15, 2024 | This sequence change affects the initiator methionine of the RAD50 mRNA. The next in-frame methionine is located at codon 7. This variant is present in population databases (rs377260382, gnomAD 0.01%). Disruption of the initiator codon has been observed in individual(s) with breast cancer and/or clinical features of Nijmegen breakage syndrome-like disorder (PMID: 26023681, 26094658; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 128024). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Nijmegen breakage syndrome-like disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 20, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PROVEAN
Benign
N;D
REVEL
Uncertain
Sift
Benign
T;D
Sift4G
Pathogenic
D;T
Polyphen
D;.
Vest4
MutPred
Gain of catalytic residue at M1 (P = 0.0135);Gain of catalytic residue at M1 (P = 0.0135);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at