5-132557325-A-G

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_005732.4(RAD50):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RAD50 NM_005732.4 start_lost
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.10

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 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_005732.4 (RAD50) was described as [Likely_pathogenic] in ClinVar as 128024
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-132557325-A-G is Pathogenic according to our data. Variant chr5-132557325-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 229813.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.1A>G	p.Met1?	start_lost	1/25	ENST00000378823.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD50	ENST00000378823.8	c.1A>G	p.Met1?	start_lost	1/25	1	NM_005732.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 23, 2016	The p.M1? variant (also known as c.1A>G), located in coding exon 1 of the RAD50 gene, results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. However, the RAD50 gene contains a second methionine 21 nucleotides (seven amino acids) downstream of the canonical start site. This has the potential to function as an alternate translation initiation site, resulting in the removal of the first six amino acids from protein, however, direct evidence is unavailable. A similar alteration at the same initiation codon, p.M1? (c.3G>A), has been reported in 1/104 Irish familial breast cancer families and 0/140 controls (Aloraifi F et al. FEBS J., 2015 Sep;282:3424-37), and has also been reported in conjunction with a BRCA2 mutation in an individual diagnosed with breast cancer at age 49 (Foley SB et al. EBioMedicine, 2015 Jan;2:74-81). In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, the p.M1? variant is interpreted as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 12, 2021	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. ClinVar contains an entry for this variant (Variation ID: 229813). A different variant (c.3G>A) giving rise to the same protein effect has been determined to be pathogenic (PMID: 26023681, 26094658; Invitae). This suggests that this variant is also likely to be causative of disease. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the RAD50 mRNA. The next in-frame methionine is located at codon 7. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Benign	-0.70	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-0.96	N;D
Sift	Uncertain	0.013	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.92
MutPred		0.99		Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);
MVP		0.72
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs876658212; hg19: chr5-131893017;