rs1060501933

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr5-132642195-C-A
• chr5-132642195-C-T
• chr5-132642195-C-G

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+12 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 12 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2PP5_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 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Non-NMD frameshift: ≥4 downstream pathogenic — very strong evidence preserved (PVS1); Stop-gained (exon 25 of 25) at amino acid 1257 of 1312; NMD not predicted. 11 pathogenic variants downstream support preserved loss-of-function impact.
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000072 — very rare for AD+AR gene (base 0.0001, raised to 0.000198 by highest known P/LP ClinVar AF 0.000198) — PM2 moderate.
	PP5Reputable source reports pathogenic		ClinVar 1-star pathogenic — moderate (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 1 star(s).

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