rs878854797

Positions:

• chr5-132618170-AAGAAAGAA-AT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_005732.4(RAD50):​c.3266_3273delinsT​(p.Lys1089IlefsTer17) 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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAD50 NM_005732.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.15

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 12 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 5-132618171-AGAAAGAA-T is Pathogenic according to our data. Variant chr5-132618171-AGAAAGAA-T is described in ClinVar as [Pathogenic]. Clinvar id is 240235.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD50	NM_005732.4	c.3266_3273delinsT	p.Lys1089IlefsTer17	frameshift_variant	21/25	ENST00000378823.8	NP_005723.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD50	ENST00000378823.8	c.3266_3273delinsT	p.Lys1089IlefsTer17	frameshift_variant	21/25	1	NM_005732.4	ENSP00000368100	P1
RAD50	ENST00000533482.5	c.*2892_*2899delinsT		3_prime_UTR_variant, NMD_transcript_variant	21/25	1		ENSP00000431225
RAD50	ENST00000651249.1	c.102_109delinsT	p.Lys35IlefsTer17	frameshift_variant	1/6			ENSP00000498257

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2016

This sequence change deletes 8 nucleotides and inserts 1 nucleotide in exon 21 of the RAD50 mRNA (c.3266_3273delinsT), causing a frameshift at codon 1089. This creates a premature translational stop signal (p.Lys1089Ilefs*17) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, truncating variants in RAD50 are known to be pathogenic (PMID: 19409520, 16385572). For these reasons, this variant has been classified as Pathogenic. -

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: rs878854797; hg19: chr5-131953863;