chr5-132604806-T-C

Position:

chr5-132604806-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_005732.4(RAD50):c.2525T>C(p.Val842Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000402 in 1,604,444 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00042 ( 1 hom. )

Consequence

RAD50
NM_005732.4 missense, splice_region

Scores

Splicing: ADA: 0.005357

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 4.66

Variant links:

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 links:

ENSG00000283782 (HGNC:):

ENSG00000283782 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11292598).

BP6

Variant 5-132604806-T-C is Benign according to our data. Variant chr5-132604806-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128005.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD50	NM_005732.4 linkuse as main transcript	c.2525T>C	p.Val842Ala	missense_variant, splice_region_variant	16/25	ENST00000378823.8	NP_005723.2	Q92878-1A5D6Y3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD50	ENST00000378823.8 linkuse as main transcript	c.2525T>C	p.Val842Ala	missense_variant, splice_region_variant	16/25	1	NM_005732.4	ENSP00000368100.4		Q92878-1
ENSG00000283782	ENST00000640655.2 linkuse as main transcript	c.2228T>C	p.Val743Ala	missense_variant, splice_region_variant	17/26	5		ENSP00000491596.2		A0A1W2PQ90

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000105

AC:

AN:

248368

Hom.:

AF XY:

0.0000819

AC XY:

AN XY:

134234

show subpopulations

Gnomad AFR exome

AF:

0.000187

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:

0.00

Gnomad NFE exome

AF:

0.000205

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000424

AC:

616

AN:

1452226

Hom.:

Cov.:

AF XY:

0.000415

AC XY:

300

AN XY:

722910

show subpopulations

Gnomad4 AFR exome

AF:

0.000151

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:

0.00

Gnomad4 NFE exome

AF:

0.000536

Gnomad4 OTH exome

AF:

0.000316

GnomAD4 genome

AF:

0.000191

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000300

Hom.:

Bravo

AF:

0.000185

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 28, 2023	The p.V842A variant (also known as c.2525T>C) is located in coding exon 16 of the RAD50 gene. The valine at codon 842 is replaced by alanine, an amino acid with similar properties. This change occurs in the first base pair of coding exon 16. This variant has been reported in multiple breast cancer case-control studies (Tommiska J et al. Int. J. Cancer, 2006 Jun;118:2911-6; Damiola F et al. Breast Cancer Res, 2014 Jun;16:R58; Young EL et al. J Med Genet, 2016 06;53:366-76). It has also been reported in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 19, 2014

RAD50 has been only recently described in association with cancer predisposition and the risks are not well understood. This variant is denoted RAD50 c.2525T>C at the cDNA level, p.Val842Ala (V842A) at the protein level, and results in the change of a Valine to an Alanine (GTT>GCT). This variant was observed in an individual with breast cancer and a family history of breast cancer (Tommiska 2006). RAD50 Val842Ala was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. This variant is a conservative substitution of one neutral non-polar amino acid for another, altering a position that is well conserved through mammals and is located in a potential coil-coiled region (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. -

Nijmegen breakage syndrome-like disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Oct 07, 2021

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 05, 2020

Variant summary: RAD50 c.2525T>C (p.Val842Ala) results in a non-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. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00011 in 279768 control chromosomes, predominantly at a frequency of 0.0002 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3.2 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. c.2525T>C has been reported in the literature in individuals affected with breast cancer or non-Hodgkin lymphoma (Tommiska_2006, Schuetz_2009, Damiola_2014). These reports 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. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

.;.;.;T

Eigen

Benign

-0.0011

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.92

.;.;D;D

M_CAP

Benign

0.0052

MetaRNN

Benign

0.11

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

.;.;.;L

PrimateAI

Uncertain

0.60

REVEL

Benign

0.046

Sift4G

Benign

0.65

.;.;.;T

Polyphen

0.048

.;.;.;B

Vest4

0.57

MVP

0.48

ClinPred

0.21

GERP RS

5.0

Varity_R

0.084

gMVP

0.20

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0054

dbscSNV1_RF

Benign

0.066

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over