rs377260382

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

Scores

6
5
5

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 9.76
Variant links:
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]

Genome browser will be placed here

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
RAD50NM_005732.4 linkuse as main transcriptc.3G>A p.Met1? start_lost 1/25 ENST00000378823.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RAD50ENST00000378823.8 linkuse as main transcriptc.3G>A p.Met1? start_lost 1/251 NM_005732.4 P1Q92878-1

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152244
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000477
AC:
12
AN:
251490
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135922
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000105
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000120
AC:
176
AN:
1461810
Hom.:
1
Cov.:
34
AF XY:
0.000110
AC XY:
80
AN XY:
727210
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000147
Gnomad4 OTH exome
AF:
0.000215
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152244
Hom.:
0
Cov.:
33
AF XY:
0.0000403
AC XY:
3
AN XY:
74382
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000132
Hom.:
0
Bravo
AF:
0.0000604
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.000109
EpiControl
AF:
0.000119

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 submitterclinical testingAmbry GeneticsJun 24, 2024The 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 15, 2024This 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 submitterclinical testingRevvity Omics, RevvityMar 20, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.48
D
BayesDel_noAF
Pathogenic
0.18
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.56
D;T
Eigen
Pathogenic
0.85
Eigen_PC
Pathogenic
0.87
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Benign
0.037
D
MetaRNN
Pathogenic
0.77
D;D
MetaSVM
Benign
-0.70
T
MutationTaster
Benign
1.0
D;D
PROVEAN
Benign
-0.63
N;D
REVEL
Uncertain
0.59
Sift
Benign
0.25
T;D
Sift4G
Pathogenic
0.0
D;T
Polyphen
1.0
D;.
Vest4
0.92
MutPred
0.99
Gain of catalytic residue at M1 (P = 0.0135);Gain of catalytic residue at M1 (P = 0.0135);
MVP
0.73
ClinPred
0.95
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
gMVP
0.65

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs377260382; hg19: chr5-131893019; COSMIC: COSV54754365; COSMIC: COSV54754365; API