17-58694980-A-G

Position:

• chr17-58694980-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_058216.3(RAD51C):​c.195A>G​(p.Arg65=) variant causes a synonymous change. The variant allele was found at a frequency of 0.000915 in 1,614,146 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R65R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00086 (23 hom.)
• Consequence: RAD51C NM_058216.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 3.64

Genes affected

RAD51C (HGNC:9820): (RAD51 paralog C) This gene is a member of the RAD51 family. RAD51 family members are highly similar to bacterial RecA and Saccharomyces cerevisiae Rad51 and are known to be involved in the homologous recombination and repair of DNA. This protein can interact with other RAD51 paralogs and is reported to be important for Holliday junction resolution. Mutations in this gene are associated with Fanconi anemia-like syndrome. This gene is one of four localized to a region of chromosome 17q23 where amplification occurs frequently in breast tumors. Overexpression of the four genes during amplification has been observed and suggests a possible role in tumor progression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 17-58694980-A-G is Benign according to our data. Variant chr17-58694980-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 136157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-58694980-A-G is described in Lovd as [Benign]. Variant chr17-58694980-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00141 (215/152318) while in subpopulation EAS AF= 0.036 (187/5190). AF 95% confidence interval is 0.0318. There are 7 homozygotes in gnomad4. There are 107 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD51C	NM_058216.3	c.195A>G	p.Arg65=	synonymous_variant	2/9	ENST00000337432.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51C	ENST00000337432.9	c.195A>G	p.Arg65=	synonymous_variant	2/9	1	NM_058216.3	P2

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 217 AN: 152200 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0363

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00303 AC: 762 AN: 251446 Hom.: 20 AF XY: 0.00267 AC XY: 363 AN XY: 135904

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0405

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000863 AC: 1262 AN: 1461828 Hom.: 23 Cov.: 31 AF XY: 0.000799 AC XY: 581 AN XY: 727218

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0294

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.000729

GnomAD4 genome AF: 0.00141 AC: 215 AN: 152318 Hom.: 7 Cov.: 32 AF XY: 0.00144 AC XY: 107 AN XY: 74476

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0360

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000390 Hom.: 1

Bravo AF: 0.00176

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 16, 2021	- -
Likely benign, no assertion criteria provided	curation	Leiden Open Variation Database	Aug 25, 2011	Curator: Arleen D. Auerbach. Submitter to LOVD: Ian Campbell. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 05, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 07, 2021	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 22, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 27, 2016	Variant summary: The RAD51C c.195A>G (p.Arg65Arg) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 354/122132 control chromosomes (13 homozygotes), predominantly observed in the East Asian subpopulation at a frequency of 0.0396715 (343/8646). This frequency is about 635 times the estimated maximal expected allele frequency of a pathogenic RAD51C variant (0.0000625), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. This variant has been reported in HBOC families, without strong evidence for causality. In addition, multiple clinical diagnostic laboratories classified this variant as benign. Taken together, this variant is classified as benign. -

Breast-ovarian cancer, familial, susceptibility to, 3 Benign:3

Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 05, 2023	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -
Benign, criteria provided, single submitter	clinical testing	Counsyl	May 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 13, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 27, 2014	This alteration is classified as 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. -

Fanconi anemia complementation group O Benign:2

Benign, criteria provided, single submitter	clinical testing	Counsyl	May 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Nov 09, 2021

- -

Fanconi anemia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

RAD51C, EXON 02, c.195A>G, p.Arg65=, Heterozygous, Benign The RAD51C p.Arg65= variant was identified in 4 of 5232 proband chromosomes (frequency: 0.001) from individuals or families with breast and ovarian cancers of Australian and Danish ethnicity and was not identified in 427 control chromosomes from healthy individuals (Jonson 2015, Thompson 2012). The variant was also identified in dbSNP (ID: rs45511291) as “With Likely benign allele”; in the ClinVar and Clinvitae database as benign by Invitae, GeneDx, Ambry Genetics, and Counsyl, and likely benign by Illumina; and in the LOVD 3.0 database 2X with the following statistical data given: 2 of 1053 (freq.=0.002) and 1 of 134 (freq.0.003). The variant was further identified in the 1000 Genomes Project in 41 of 5000 chromosomes (frequency: 0.001); in HAPMAP-EAS in 40 of 1008 chromosomes (frequency: 0.04), HAPMAP-AFR in 1 of 1322 chromosomes (frequency: 0.0001) and the NHLBI GO Exome Sequencing Project in 1 of 8600 European American and in 5 of 4406 African American alleles. The variant was not identified in the Cosmic and MutDB, databases. The variant was identified in control databases in 773 of 277228 chromosomes at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following population at a frequency greater than 1%: East Asian in 748 of 18868 chromosomes (freq: 0.04). The p.Arg65= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. REFERENCES: Jønson L, Ahlborn LB, Steffensen AY, Djursby M, Ejlertsen B, Timshel S,Nielsen FC, Gerdes AM, Hansen TV. Identification of six pathogenic RAD51Cmutations via mutational screening of 1228 Danish individuals with increased riskof hereditary breast and/or ovarian cancer. Breast Cancer Res Treat. 2016Jan;155(2):215-22. doi: 10.1007/s10549-015-3674-y. Epub 2016 Jan 6. PubMed PMID: 26740214. Thompson ER, Boyle SE, Johnson J, Ryland GL, Sawyer S, Choong DY, kConFab,Chenevix-Trench G, Trainer AH, Lindeman GJ, Mitchell G, James PA, Campbell IG.Analysis of RAD51C germline mutations in high-risk breast and ovarian cancerfamilies and ovarian cancer patients. Hum Mutat. 2012 Jan;33(1):95-9. doi:10.1002/humu.21625. Epub 2011 Nov 4. PubMed PMID: 21990120. -

Breast and Ovarian Cancer Susceptibility Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	12
DANN	Benign	0.83

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: rs45511291; hg19: chr17-56772341;