NM_005732.4:c.3770C>A

Variant names:

• chr5-132642195-C-A
• rs1060501933
• NM_005732.4:c.3770C>A
• RAD50 p.Ser1257*

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+8 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 8 classification points (ACGS-UK Somatic Oncogenicity v2025). O1_SupportingO2_StrongO3_SupportingO9_Moderate

The NM_005732.4(RAD50):c.3770C>A (p.Ser1257*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. This is a loss-of-function variant that does not trigger NMD. The gene RAD50 is a tumor suppressor gene (CancerMine: 1 TSG, 1 oncogene, 1 driver citations). The gene RAD50 is a known oncogene (CancerMine: 1 TSG, 1 oncogene, 1 driver citations). The gene RAD50 is a cancer driver gene (CancerMine: 1 TSG, 1 oncogene, 1 driver citations). The variant allele was found at a cumulative frequency of 0.00000205 (AC=3) in the gnomAD database across 1,461,726 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000072. In-silico predictor (BayesDel (noAF)) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RAD50 NM_005732.4 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.78
• Publications: 2 publications found

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]

RAD50 Gene-Disease associations (from GenCC):

• Nijmegen breakage syndrome-like disorder

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, PanelApp Australia
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000283782 (HGNC:):

TH2LCRR (HGNC:40495): ()

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Likely_pathogenic. The variant received 8 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O1Established oncogenic variant		TSG gene: ClinVar germline P/LP (single/no review) — Supporting (O1); O1 contributing sources (1.0 pts): ClinVar germline P/LP in TSG (★)
	O2Null variant in tumour suppressor gene		Non-NMD frameshift: ≥4 pathogenic in truncated region — O2 strong (+4); Use caution in the presence of multiple transcripts; Gene confirmed as TSG in CancerMine (TSG: 1 citations, oncogene: 1 citations, driver: 1 citations).; Frameshift/stop-gained. NMD predicted: false. LoF mechanism: true. Downstream pathogenic count: 11.
	O3Absent or very rare in population		Very rare in gnomAD (popmax AF <0.01%) — O3 supporting; GnomAD effective popmax AF = 0.000001 — very rare (O3 supporting [+1])
	O9Protein length change in non-repeat region		Truncating variant in final exon of oncogene — predicted GOF (O9 moderate); Truncating variant in final exon of oncogene — predicted to escape NMD and result in GOF

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_005732.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RAD50 NM_005732.4	MANE Select	c.3770C>A p.Ser1257*	stop_gained	Exon 25 of 25	Prot: NP_005723.2
	TH2LCRR NR_132125.1		n.189+3G>T	splice_regionintron	Intron 2 of 2	Prot:
	TH2LCRR NR_132126.1		n.175-3930G>T	intron	Intron 1 of 1	Prot:

RAD50 NM_005732.4

MANE Select

HGVSc / HGVSpc.3770C>Ap.Ser1257*

Exon rankExon 25 of 25

stop_gained

Prot: NP_005723.2

TH2LCRR NR_132125.1

HGVSc / HGVSpn.189+3G>T

Exon rankIntron 2 of 2

splice_regionintron

Prot:

TH2LCRR NR_132126.1

HGVSc / HGVSpn.175-3930G>T

Exon rankIntron 1 of 1

intron

Prot:

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RAD50 ENST00000378823.8	TSL:1MANE Select	c.3770C>A p.Ser1257*	stop_gained	Exon 25 of 25	Prot: ENSP00000368100.4 UniProt:
	ENSG00000283782 ENST00000638452.2	TSL:5	c.3473C>A p.Ser1158*	stop_gained	Exon 27 of 27	Prot: ENSP00000492349.2 UniProt:
	TH2LCRR ENST00000458509.1	TSL:1	n.189+3G>T	splice_regionintron	Intron 2 of 2	Prot:

RAD50 ENST00000378823.8

TSL:1MANE Select

HGVSc / HGVSpc.3770C>Ap.Ser1257*

Exon rankExon 25 of 25

stop_gained

Prot: ENSP00000368100.4UniProt: Q92878-1

ENSG00000283782 ENST00000638452.2

TSL:5

HGVSc / HGVSpc.3473C>Ap.Ser1158*

Exon rankExon 27 of 27

stop_gained

Prot: ENSP00000492349.2UniProt: A0A1W2PQ90

TH2LCRR ENST00000458509.1

TSL:1

HGVSc / HGVSpn.189+3G>T

Exon rankIntron 2 of 2

splice_regionintron

Prot:

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD2 exomes	AF: 0.00000398	AC:1	Hom:	AN:251298	Cov:
GnomAD4 exome	AF: 0.00000205	AC:3	Hom:0	AN:1461726	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000287	AC:1	Hom:0	AN:34852	Cov:

Showing 5 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.00	0	67870	0.00000750	1	133330

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary cancer-predisposing syndrome (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	42
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
GPN-Star LLR	N/A	-11
GPN-Star score	N/A	11
Mutation Taster	N/A	7/193	disease causing (ClinVar)
PhyloP100	Uncertain	5.8

Showing 12 of 12 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.17
Pangolin loss	Benign	0.17	Position offset: -17
SpliceAI score (max)	Benign	0.060	Details are displayed if max score is > 0.2

Showing 3 of 3 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1060501933;

hg19: chr5-131977887;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar