5-132618209-G-C

Variant names:

• chr5-132618209-G-C
• rs1554099877
• NM_005732.4:c.3304G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005732.4(RAD50):​c.3304G>C​(p.Glu1102Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. E1102D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAD50 NM_005732.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.15
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

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

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD50	NM_005732.4	MANE Select	c.3304G>C	p.Glu1102Gln	missense	Exon 21 of 25	NP_005723.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD50	ENST00000378823.8	TSL:1 MANE Select	c.3304G>C	p.Glu1102Gln	missense	Exon 21 of 25	ENSP00000368100.4
	ENSG00000283782	ENST00000638452.2	TSL:5	c.3007G>C	p.Glu1003Gln	missense	Exon 23 of 27	ENSP00000492349.2
	RAD50	ENST00000533482.5	TSL:1	n.*2930G>C		non_coding_transcript_exon	Exon 21 of 25	ENSP00000431225.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Aug 29, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E1102Q variant (also known as c.3304G>C), located in coding exon 21 of the RAD50 gene, results from a G to C substitution at nucleotide position 3304. The glutamic acid at codon 1102 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0037	T
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.8	L
PhyloP100		9.2
PrimateAI	Uncertain	0.56	T
REVEL	Benign	0.20
Sift4G	Benign	0.17	T
Polyphen		0.57	P
Vest4		0.54
MutPred		0.36		Gain of MoRF binding (P = 0.0477)
MVP		0.54
ClinPred		0.99	D
GERP RS		5.4
PromoterAI		-0.0072	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.28
gMVP		0.74
Mutation Taster		=68/32	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: rs1554099877; hg19: chr5-131953901;