5-132557327-G-C

Variant names:

• chr5-132557327-G-C
• rs377260382
• NM_005732.4:c.3G>C
• RAD50 p.Met1?

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+6 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 6 classification points (ACMG Germline Pathogenicity v2019). PVS1_ModeratePS1_ModeratePM2

The NM_005732.4(RAD50):c.3G>C (p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant disrupts the start codon, preventing normal translation initiation. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.76). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RAD50 NM_005732.4 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.76
• Publications: 9 publications found

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]

RAD50 Gene-Disease associations (from GenCC):

• Nijmegen breakage syndrome-like disorder

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, PanelApp Australia
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000283782 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Likely_pathogenic. The variant received 6 points.

• PVS1: Start-lost with downstream start: ≥2 pathogenic between starts — moderate ; Start codon lost (exon 1 of 25); downstream rescue start codon present, with 4 pathogenic variants between start codons.
• PS1: Different start-lost, 1–2-star ClinVar pathogenic — moderate (PS1); ClinVar contains 2 P/LP entries with the start-lost variant at the same initiation codon (highest review level: 2 stars).
• PM2: Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.000198 by highest known P/LP ClinVar AF 0.000198) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_005732.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD50	NM_005732.4	MANE Select	c.3G>C	p.Met1?	start_lost	Exon 1 of 25	NP_005723.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD50	ENST00000378823.8	TSL:1 MANE Select	c.3G>C	p.Met1?	start_lost	Exon 1 of 25	ENSP00000368100.4	Q92878-1
	ENSG00000283782	ENST00000638452.2	TSL:5	c.-168-1957G>C		intron	N/A	ENSP00000492349.2	A0A1W2PQ90
	RAD50	ENST00000416135.5	TSL:1	c.-169+854G>C		intron	N/A	ENSP00000389515.1	C9JNH8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.70	T
PhyloP100		9.8
PROVEAN	Benign	-0.63	N
REVEL	Uncertain	0.57
Sift	Benign	0.25	T
Sift4G	Pathogenic	0.0	D
PromoterAI		-0.080	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.65
Mutation Taster		=50/150	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs377260382;

hg19: chr5-131893019;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar