rs760146707

Positions:

• chr5-132579996-GT-G

Variant summary

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

The NM_005732.4(RAD50):​c.687del​(p.Ser229ArgfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000177 in 1,613,386 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S229S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: RAD50 NM_005732.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.206

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 5-132579996-GT-G is Pathogenic according to our data. Variant chr5-132579996-GT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 185010.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.687del	p.Ser229ArgfsTer6	frameshift_variant	5/25	ENST00000378823.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD50	ENST00000378823.8	c.687del	p.Ser229ArgfsTer6	frameshift_variant	5/25	1	NM_005732.4	P1

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000462 AC: 116 AN: 251160 Hom.: 0 AF XY: 0.000442 AC XY: 60 AN XY: 135762

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00462

Gnomad NFE exome AF: 0.0000969

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000153 AC: 224 AN: 1461080 Hom.: 0 Cov.: 31 AF XY: 0.000161 AC XY: 117 AN XY: 726894

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00395

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.000658 AC XY: 49 AN XY: 74486

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00565

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 28, 2023	The c.687delT pathogenic mutation, located in coding exon 5 of the RAD50 gene, results from a deletion of one nucleotide at nucleotide position 687, causing a translational frameshift with a predicted alternate stop codon (p.S229Rfs*6). This alteration was first reported in 2/151 Finnish familial breast/ovarian cancer individuals as well as in 6/1000 cancer free controls (Heikkinen K, J. Med. Genet. 2003 Dec; 40(12):e131). In a case control study of 317 consecutive newly diagnosed Finnish breast cancer patients and 1000 geographically matched healthy controls, eight breast cancer patients and six controls were carriers (95% CI 1.5–12.5, P = 0.008). Haplotype analysis suggests this is a Finnish founder mutation (Heikkinen K, Carcinogenesis 2006 Aug; 27(8):1). In addition to the clinical data presented in the literature, 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 14, 2023	Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects RAD50 function (PMID: 14684699, 16385572, 16474176). ClinVar contains an entry for this variant (Variation ID: 185010). This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer in that population (PMID: 14684699, 16385572, 16474176, 25452441). It is commonly reported in individuals of Finnish ancestry (PMID: 14684699, 16385572, 16474176, 25452441). This variant is present in population databases (rs760146707, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This sequence change creates a premature translational stop signal (p.Ser229Argfs*6) 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). -

Nijmegen breakage syndrome-like disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 15, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 13, 2016	- -

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: rs760146707; hg19: chr5-131915688;