5-132587981-G-T

Position:

• chr5-132587981-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_005732.4(RAD50):​c.943G>T​(p.Val315Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00221 in 1,612,604 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (5 hom.)
• Consequence: RAD50 NM_005732.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: 7.88

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015402764).
• BP6: Variant 5-132587981-G-T is Benign according to our data. Variant chr5-132587981-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128028.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4, Benign=2}.
• BS2: High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD50	NM_005732.4	c.943G>T	p.Val315Leu	missense_variant	7/25	ENST00000378823.8	NP_005723.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD50	ENST00000378823.8	c.943G>T	p.Val315Leu	missense_variant	7/25	1	NM_005732.4	ENSP00000368100.4
ENSG00000283782	ENST00000640655.2	c.646G>T	p.Val216Leu	missense_variant	8/26	5		ENSP00000491596.2

Frequencies

GnomAD3 genomes AF: 0.00133 AC: 203 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

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: 0.00237

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.00120 AC: 299 AN: 250054 Hom.: 0 AF XY: 0.00115 AC XY: 156 AN XY: 135240

Gnomad AFR exome AF: 0.000557

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00205

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00230 AC: 3366 AN: 1460336 Hom.: 5 Cov.: 31 AF XY: 0.00218 AC XY: 1583 AN XY: 726570

Gnomad4 AFR exome AF: 0.000389

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000937

Gnomad4 NFE exome AF: 0.00288

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.00133 AC: 203 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.00118 AC XY: 88 AN XY: 74456

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00237

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.00166 Hom.: 0

Bravo AF: 0.00137

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00125 AC: 152

EpiCase AF: 0.00234

EpiControl AF: 0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2014	RAD50 has only recently been described in association with cancer predisposition and the risks are not well understood. This variant is denoted RAD50 c.943G>T at the cDNA level, p.Val315Leu (V315L) at the protein level, and results in the change of a Valine to a Leucine (GTA>TTA). This variant has been published in two individuals with familial breast cancer and in two with multiple primaries including laryngeal cancer (Tommiska 2006, Zió Kowska-Suchanek 2013). RAD50 Val315Leu was also reported in one healthy control in Zió Kowska-Suchanek et al (2013). This variant was observed with an allele frequency of 0.3% (23/8600) in European Americans in the NHLBI Exome Sequencing Project, not frequent enough to be considered a polymorphism. This variant is a conservative substitution of one neutral non-polar amino acid for another, altering a position that is well conserved throughout evolution and is located in the coiled-coil region per UniProt. In silico analyses predict this variant to have a benign effect on protein structure and function. At a molecular level, the impact of this missense variant on protein structure and function is not known and thus we consider this to be a variant of uncertain significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and the RAD50 gene, remain unclear. -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 22, 2023	- -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 09, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 22, 2021	Variant summary: RAD50 c.943G>T (p.Val315Leu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 251062 control chromosomes. The observed variant frequency is approximately 19 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD50 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (6.3e-05), strongly suggesting that the variant is benign. c.943G>T has been reported in the literature in individuals affected with a variety of cancers such as breast cancer, multiple primary tumors as well as unaffected control cohorts (example, Harvey_2017, Tommiska_2006, Young_2016, Ziolkowska-Suchanek_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign, n=1, likely benign, n=1, VUS, n=1). Based on the evidence outlined above, the variant was classified as benign. -

Nijmegen breakage syndrome-like disorder Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	May 15, 2023	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Apr 20, 2021	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 17, 2018	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.074	.;.;.;T;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;.;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.015	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	.;.;.;M;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.74	.;.;.;.;N
REVEL	Benign	0.20
Sift	Benign	0.41	.;.;.;.;T
Sift4G	Benign	0.25	.;.;.;T;T
Polyphen		0.78	.;.;.;P;.
Vest4		0.51
MutPred		0.21		.;.;.;Loss of MoRF binding (P = 0.0988);Loss of MoRF binding (P = 0.0988);
MVP		0.47
ClinPred		0.028	T
GERP RS		5.4
Varity_R		0.24
gMVP		0.33

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: rs28903090; hg19: chr5-131923673; COSMIC: COSV99037104; COSMIC: COSV99037104;