5-132595759-TAA-TA

Variant names:

• chr5-132595759-TA-T
• rs397507178
• NM_005732.4:c.2165delA

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_005732.4(RAD50):​c.2165delA​(p.Lys722ArgfsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000748 in 1,444,452 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000075 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RAD50 NM_005732.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -0.126

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 Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 5-132595759-TA-T is Pathogenic according to our data. Variant chr5-132595759-TA-T is described in ClinVar as [Pathogenic]. Clinvar id is 408407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132595759-TA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD50	NM_005732.4	c.2165delA	p.Lys722ArgfsTer14	frameshift_variant	Exon 13 of 25	ENST00000378823.8	NP_005723.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD50	ENST00000378823.8	c.2165delA	p.Lys722ArgfsTer14	frameshift_variant	Exon 13 of 25	1	NM_005732.4	ENSP00000368100.4
ENSG00000283782	ENST00000640655.2	c.1868delA	p.Lys623ArgfsTer14	frameshift_variant	Exon 14 of 26	5		ENSP00000491596.2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 4 AN: 150312 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.0000488

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000665

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000748 AC: 108 AN: 1444452 Hom.: 0 Cov.: 31 AF XY: 0.0000709 AC XY: 51 AN XY: 718916

Gnomad4 AFR exome AF: 0.0000606

Gnomad4 AMR exome AF: 0.0000452

Gnomad4 ASJ exome AF: 0.0000390

Gnomad4 EAS exome AF: 0.000154

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.000366

Gnomad4 NFE exome AF: 0.0000673

Gnomad4 OTH exome AF: 0.0000336

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000266 AC: 4 AN: 150312 Hom.: 0 Cov.: 32 AF XY: 0.0000273 AC XY: 2 AN XY: 73298

Gnomad4 AFR AF: 0.0000488

Gnomad4 AMR AF: 0.0000665

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000384 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Jul 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Lys722Argfs*14) 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: 19409520). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 32868316, 35220195). This variant is also known as c.2157delA, c.2157del. ClinVar contains an entry for this variant (Variation ID: 408407). For these reasons, this variant has been classified as Pathogenic. -

Apr 28, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2165delA variant, located in coding exon 13 of the RAD50 gene, results from a deletion of one nucleotide at nucleotide position 2165, causing a translational frameshift with a predicted alternate stop codon (p.K722Rfs*14). 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

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: rs397507178; hg19: chr5-131931451;