chr5-132642195-C-T

Variant names:

• chr5-132642195-C-T
• rs1060501933
• NM_005732.4:c.3770C>T
• RAD50 p.Ser1257Leu

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Moderate

The NM_005732.4(RAD50):c.3770C>T (p.Ser1257Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.S1257A: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 183984); p.S1257P: Uncertain_significance (ClinVar VariationId 954365, 1 star)

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAD50 NM_005732.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.78
• Publications: 0 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: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.000198 by highest known P/LP ClinVar AF 0.000198) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

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>T p.Ser1257Leu	missense	Exon 25 of 25	Prot: NP_005723.2
	TH2LCRR NR_132125.1		n.189+3G>A	splice_regionintron	Intron 2 of 2	Prot:
	TH2LCRR NR_132126.1		n.175-3930G>A	intron	Intron 1 of 1	Prot:

RAD50 NM_005732.4

MANE Select

HGVSc / HGVSpc.3770C>Tp.Ser1257Leu

Exon rankExon 25 of 25

missense

Prot: NP_005723.2

TH2LCRR NR_132125.1

HGVSc / HGVSpn.189+3G>A

Exon rankIntron 2 of 2

splice_regionintron

Prot:

TH2LCRR NR_132126.1

HGVSc / HGVSpn.175-3930G>A

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>T p.Ser1257Leu	missense	Exon 25 of 25	Prot: ENSP00000368100.4 UniProt:
	ENSG00000283782 ENST00000638452.2	TSL:5	c.3473C>T p.Ser1158Leu	missense	Exon 27 of 27	Prot: ENSP00000492349.2 UniProt:
	TH2LCRR ENST00000458509.1	TSL:1	n.189+3G>A	splice_regionintron	Intron 2 of 2	Prot:

RAD50 ENST00000378823.8

TSL:1MANE Select

HGVSc / HGVSpc.3770C>Tp.Ser1257Leu

Exon rankExon 25 of 25

missense

Prot: ENSP00000368100.4UniProt: Q92878-1

ENSG00000283782 ENST00000638452.2

TSL:5

HGVSc / HGVSpc.3473C>Tp.Ser1158Leu

Exon rankExon 27 of 27

missense

Prot: ENSP00000492349.2UniProt: A0A1W2PQ90

TH2LCRR ENST00000458509.1

TSL:1

HGVSc / HGVSpn.189+3G>A

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	24
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.97	D
FuncVEP CTI	Benign	0.16
GPN-Star LLR	N/A	-8.5
GPN-Star score	N/A	8.5
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-1.1	T
Mutation Taster	N/A	71/29	polymorphism
MutationAssessor	Uncertain	2.6	M
PhyloP100	Uncertain	5.8
popEVE	Benign	-3.9
PrimateAI	Pathogenic	0.86	D
REVEL	Benign	0.14
Sift4G	Benign	0.11	T
Varity_R	N/A	0.41
VESM-3B	Benign	-9.7

Showing 26 of 26 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 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