5-132591378-C-G

Variant names:

• chr5-132591378-C-G
• rs1554098423
• NM_005732.4:c.1607C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005732.4(RAD50):​c.1607C>G​(p.Thr536Ser) 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 (★★).

• 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: 7.38

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]

ENSG00000283782 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD50	NM_005732.4	c.1607C>G	p.Thr536Ser	missense_variant	Exon 10 of 25	ENST00000378823.8	NP_005723.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD50	ENST00000378823.8	c.1607C>G	p.Thr536Ser	missense_variant	Exon 10 of 25	1	NM_005732.4	ENSP00000368100.4
ENSG00000283782	ENST00000640655.2	c.1310C>G	p.Thr437Ser	missense_variant	Exon 11 of 26	5		ENSP00000491596.2

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:2

Nov 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T536S variant (also known as c.1607C>G), located in coding exon 10 of the RAD50 gene, results from a C to G substitution at nucleotide position 1607. The threonine at codon 536 is replaced by serine, an amino acid with 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. -

Aug 19, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with RAD50-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with serine at codon 536 of the RAD50 protein (p.Thr536Ser). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	.;.;.;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	.;.;D;D
M_CAP	Benign	0.0062	T
MetaRNN	Uncertain	0.50	D;D;D;D
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.3	.;.;.;M
PrimateAI	Uncertain	0.67	T
REVEL	Benign	0.23
Sift4G	Benign	0.45	.;.;.;T
Polyphen		0.046	.;.;.;B
Vest4		0.64
MutPred		0.20		.;.;.;Gain of catalytic residue at T536 (P = 0.059);
MVP		0.65
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.21
gMVP		0.21

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554098423; hg19: chr5-131927070;