5-132557329-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_005732.4(RAD50):c.5C>T(p.Ser2Phe) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RAD50 NM_005732.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 7.72

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 5-132557329-C-T is Benign according to our data. Variant chr5-132557329-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 527368.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD50	NM_005732.4	c.5C>T	p.Ser2Phe	missense_variant	1/25	ENST00000378823.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD50	ENST00000378823.8	c.5C>T	p.Ser2Phe	missense_variant	1/25	1	NM_005732.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	research	University of Washington Department of Laboratory Medicine, University of Washington	Aug 27, 2018	The RAD50 variant designated as NM_005732.3:c.5C>T (p.Ser2Phe) is classified as likely benign. RAD50 has been associated with a small increase in breast cancer risk in some studies (Damiola et al, 2014, PMID: 24894818; Rebbeck et al 2011, PMID: 21799032), but found not to be associated with breast cancer in others (Couch et al. 2017, PMID: 28418444). In one observed family the RAD50 p.Ser2Phe variant was found not to segregate with breast cancer, as the variant was inherited paternally when close relatives with breast cancer were on the maternal side of the family. This indicates that the variant is less likely to cause breast cancer. In addition, this variant is not found in a key functional domain where other missense variants that are suspected to be associated with breast cancer have been identified (Damiola et al, 2014, PMID: 24894818). This variant is not listed in population databases. It is listed in the ClinVar database (Variation ID: 527368). Computer software programs have conflicting predictions on whether this variant is likely to be tolerated. The combined results are consistent with a classification of likely benign. This variant is not predicted to alter RAD50 function or modify cancer risk. A modest (less than 2-fold) increase in cancer risk due to this variant cannot be excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	May 24, 2018	This sequence change replaces serine with phenylalanine at codon 2 of the RAD50 protein (p.Ser2Phe). The serine residue is moderately conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RAD50-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.10
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Pathogenic	3.5	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.43
MutPred		0.31		Loss of phosphorylation at S2 (P = 0.011);Loss of phosphorylation at S2 (P = 0.011);
MVP		0.71
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.96
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1554096631; hg19: chr5-131893021;