chr5-132587583-C-T

Variant names:

• chr5-132587583-C-T
• rs1554098158
• NM_005732.4:c.778C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005732.4(RAD50):​c.778C>T​(p.His260Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H260R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAD50 NM_005732.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.783
• 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• familial ovarian cancer

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000283782 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06613204).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD50	NM_005732.4	c.778C>T	p.His260Tyr	missense_variant	Exon 6 of 25	ENST00000378823.8	NP_005723.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD50	ENST00000378823.8	c.778C>T	p.His260Tyr	missense_variant	Exon 6 of 25	1	NM_005732.4	ENSP00000368100.4
ENSG00000283782	ENST00000638452.2	c.481C>T	p.His161Tyr	missense_variant	Exon 8 of 27	5		ENSP00000492349.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Mar 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.H260Y variant (also known as c.778C>T), located in coding exon 6 of the RAD50 gene, results from a C to T substitution at nucleotide position 778. The histidine at codon 260 is replaced by tyrosine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Nijmegen breakage syndrome-like disorder Uncertain:1

Dec 01, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	.;.;.;T;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.83	.;.;T;T;T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.066	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	.;.;.;N;.
PhyloP100		0.78
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.3	.;.;.;.;N
REVEL	Benign	0.065
Sift	Benign	0.067	.;.;.;.;T
Sift4G	Uncertain	0.040	.;.;.;D;D
Polyphen		0.0090	.;.;.;B;.
Vest4		0.12
MutPred		0.25		.;.;.;Gain of ubiquitination at K264 (P = 0.062);Gain of ubiquitination at K264 (P = 0.062);
MVP		0.33
ClinPred		0.15	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.081
gMVP		0.096
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1554098158; hg19: chr5-131923275;