5-132589675-TGAGATAA-TGAGATAAGAGATAA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_005732.4(RAD50):c.1300_1306dup(p.Lys436ArgfsTer2) variant causes a frameshift 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. D430D) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAD50 NM_005732.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.65

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-132589675-T-TGAGATAA is Pathogenic according to our data. Variant chr5-132589675-T-TGAGATAA is described in ClinVar as [Pathogenic]. Clinvar id is 127994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD50	NM_005732.4	c.1300_1306dup	p.Lys436ArgfsTer2	frameshift_variant	9/25	ENST00000378823.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD50	ENST00000378823.8	c.1300_1306dup	p.Lys436ArgfsTer2	frameshift_variant	9/25	1	NM_005732.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 18, 2021	This variant has not been reported in the literature in individuals with RAD50-related conditions. ClinVar contains an entry for this variant (Variation ID: 127994). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Lys436Argfs*2) in the RAD50 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAD50 are known to be pathogenic (PMID: 16385572, 19409520). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 2013	This variant is denoted RAD50 c.1306_1307insGATAAGA (aka c.1300_1306dupGATAAGA) at the cDNA level and p.Lys436ArgfsX2 (K436RfsX2) at the protein level. The surrounding sequence is ATAAGA{insGATAAGA}AAACTG. The insertion causes a frameshift, changing a Lysine to an Arginine at codon 436, and creating a premature stop codon at position 2 of the new reading frame. This variant has not been published as a pathogenic mutation or a benign polymorphism to our knowledge and was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI ESP Exome Variant Server, suggesting it is not a common benign variant in these populations. RAD50 c.1306_1307insGATAAGA is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay leading us to conclude that RAD50 c.1306_1307insGATAAGA is an expected pathogenic risk allele. The MRE11-RAD50-NBS1 complex is essential to maintaining genomic integrity based on its crucial role in DNA double-strand break repair as part of the Fanconi Anemia/BRCA pathway and variants in this gene have been published in association with breast and ovarian cancer (Heikkinen 2006, Walsh 2011). Heikkinen et al. (2006) reported a recurrent RAD50 frameshift variant identified in 8 out of 317 Finnish breast cancer patients compared with 6 out of 1000 controls. Two of these patients were considered to have familial breast cancer in which incomplete segregation was observed between the RAD50 mutation and cancer. Another novel splicing variant was observed in a case with a family history of breast cancer. The authors conclude that the incomplete segregation data and the frequency of this mutation in controls suggest that the recurrent RAD50 mutation is a low-penetrance breast cancer susceptibility allele (Heikkinen 2006). Walsh et al. (2011) also identified a RAD50 mutation carrier in 1/360 patients with ovarian cancer, peritoneal cancer, or fallopian tube cancer unselected for family history. However, based on currently available data, precise cancer risks associated with this gene are not well-described.Of note, inheritance of two pathogenic mutations in the RAD50 gene (one from each parent) may cause a rare disorder called Nijmegen breakage syndrome-like disorder (NBSLD) associated with growth retardation, microcephaly, mental retardation and a characteristic facial appearance (Waltes 2009). If a RAD50 mutation carrier's partner is also a carrier of a RAD50 mutation, the risk to have a child with NBSLD is 25% with each pregnancy. The variant is found in BR-OV-HEREDIC panel(s). -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 26, 2019	The c.1300_1306dupGATAAGA pathogenic mutation, located in coding exon 9 of the RAD50 gene, results from a duplication of GATAAGA at nucleotide position 1300, causing a translational frameshift with a predicted alternate stop codon (p.K436Rfs*2). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs587780147; hg19: chr5-131925367;