rs147241704

Positions:

• chr17-58709943-G-A
• chr17-58709943-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000337432.9(RAD51C):​c.790G>A​(p.Gly264Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00314 in 1,613,062 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G264V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0033 (16 hom.)
• Consequence: RAD51C ENST00000337432.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:25 O:1
• Conservation: PhyloP100: 7.47

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010389477).
• BP6: Variant 17-58709943-G-A is Benign according to our data. Variant chr17-58709943-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128211.We mark this variant Likely_benign, oryginal submissions are: {Benign=7, Uncertain_significance=4, Likely_benign=11, not_provided=1}. Variant chr17-58709943-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.002 (305/152166) while in subpopulation NFE AF= 0.00335 (228/68008). AF 95% confidence interval is 0.003. There are 1 homozygotes in gnomad4. There are 133 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD51C	NM_058216.3	c.790G>A	p.Gly264Ser	missense_variant	5/9	ENST00000337432.9	NP_478123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD51C	ENST00000337432.9	c.790G>A	p.Gly264Ser	missense_variant	5/9	1	NM_058216.3	ENSP00000336701	P2

Frequencies

GnomAD3 genomes AF: 0.00201 AC: 305 AN: 152048 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00335

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00175 AC: 439 AN: 251430 Hom.: 2 AF XY: 0.00173 AC XY: 235 AN XY: 135890

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.000785

Gnomad NFE exome AF: 0.00346

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00326 AC: 4758 AN: 1460896 Hom.: 16 Cov.: 30 AF XY: 0.00307 AC XY: 2232 AN XY: 726814

Gnomad4 AFR exome AF: 0.000598

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.000805

Gnomad4 NFE exome AF: 0.00411

Gnomad4 OTH exome AF: 0.00179

GnomAD4 genome AF: 0.00200 AC: 305 AN: 152166 Hom.: 1 Cov.: 30 AF XY: 0.00179 AC XY: 133 AN XY: 74386

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.000328

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000566

Gnomad4 NFE AF: 0.00335

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00325 Hom.: 1

Bravo AF: 0.00215

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00185 AC: 225

EpiCase AF: 0.00300

EpiControl AF: 0.00290

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:25 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:10 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2020	This variant is associated with the following publications: (PMID: 26406419, 24800917, 27978560, 27443514, 25980754, 26740214, 20400964, 22167183, 21750962, 22538716, 22725699, 22370629, 24315737, 21616938, 24993905, 25470109, 25318351, 24504028, 21990120, 27153395, 27621404, 27878467, 26976419, 26261251, 21537932, 27622768, 28829762, 29458332, 28678401, 23117857, 30374176, 26483394, 30309722, 31159747) -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 20, 2017	Variant summary: The c.790G>A (p.Gly264Ser) in RAD51C gene is a missense change that involves a conserved nucleotide. The variant is located within the conserved domain Rad51_DMC1_radA, but is located outside of multimer (BRC) interface. 3/4 in silico tools predict deleterious outcome and in functional studies the variant displayed hypomorphic effects with partial repair function and partially defective homologous recombination activity.(Meindl, 2010; Somyajit, 2012; Somyajit, 2015). The variant is present in the large control population dataset of ExAC and gnomAD at a similar frequencies of 0.001853 (225/121398 and 483/277178 chrs tested, respectively), predominantly in individuals of European descent (0.003410; 207/66736 and 432/126686 chrs tested), including 2 homozygotes. These frequencies exceed the maximal expected frequency of a pathogenic allele (0.0000625) in this gene. However, this variant has been cited in breast and ovarian cancer patients at greater frequency than in controls, and several publications indicate that this variant is an ovarian cancer risk allele (Song et al 2015, Loveday at al 2012, Meindl et al 2010). The odd's ratios calculated for its association with cancer across multiple independent studies have been in the range of 1.9-4, with the 95% CI including 1.0, example, OR 1.93 across all breast cancer cases with a CI of 0.5-7.46 as reported by Pelttari et al (2011). According to the ACMG guidelines if the CI includes 1.0, there is little confidence in the assertion of association. The guidelines state that studies with OR>5.0 and where the 95% CI does not include 1.0 are considered as strong evidence in favor of pathogenicity. The variant has been reported in probands from multiple HBOC families, including 3 families tested positive for disease-causing mutation in BRCA1 (p.Tyr1463Ter), BRCA2 (c.8632+1G>T) or BRCA2 (p.Lys944Ter), respectively. The variant was also identified in one internal LCA specimen in co-occurrence with a known pathogenic variant in CHEK2 (c.1100delC). Lastly, several reputable databases/clinical laboratories cite the variant with classification of Benign/Likely Benign. Taking all line of evidence into consideration, the variant was conservatively classified as Benign. -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	RAD51C: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Uncertain significance and reported on 08-11-2016 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 12, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	May 23, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 12, 2019	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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 05, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 28, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Jul 21, 2017	- -

Breast-ovarian cancer, familial, susceptibility to, 3 Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 18, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 06, 2023	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -
Likely benign, criteria provided, single submitter	research	University of Washington Department of Laboratory Medicine, University of Washington	May 09, 2018	The RAD51C variant designated as NM_058216.2: c.790G>A (p.G264S) is classified as likely benign. Cosegregation analysis of two observed families was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303). The results are a combined likelihood ratio of 1.553 (Thompson, et al., 2003, PMID:2900794), which provides supporting evidence that the variant is pathogenic. However, this variant has been reported to be present in approximately 1 in every 161 individuals with European ancestry and South Asian ancestry (exac.broadinstitute.org), which is more common than known ovarian cancer risk variants. This population frequency is not consistent with a high-risk cancer variant and supports a classification of likely benign. Additionally, this variant has been reported in multiple families with breast and ovarian cancer who also tested positive for known pathogenic mutations in BRCA1 and BRCA2. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives a less than 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter RAD51C function or modify cancer risk for breast and ovarian cancer. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This variant is not predicted to alter EPCAM function or modify risk for Lynch syndrome. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 08, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 06, 2021	- -

Hereditary breast ovarian cancer syndrome Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Sep 27, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -

Fanconi anemia complementation group O Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 18, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Jun 17, 2022

- -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jun 29, 2023

- -

Fanconi anemia complementation group O;C3150659:Breast-ovarian cancer, familial, susceptibility to, 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Counsyl

Jun 29, 2017

- -

RAD51C-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 15, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The RAD51C p.Gly264Ser variant was identified in 95 of 24,640 proband chromosomes (frequency: 0.004) from individuals or families with endometrial, pancreatic, colorectal, breast or ovarian cancer and was present in 40 of 16846 control chromosomes (frequency: 0.002) from healthy individuals (Meindl 2009, Vuorela 2011, Thompson 2012, Schekenbach 2014, Song 2015, Leeneer 2012, Loveday 2012, Coulet 2013, Cunningham 2014, Gevensleben 2014, Hu 2016, Jonson 2015 26740214, Ring 2016, Pearlman 2017). The variant was also identified in dbSNP (rs147241704) as 'Auwith other allele'Au, ClinVar (classified as uncertain significance by PreventionGenetics and 7 other submitters; as likely benign by Ambry Genetics, GeneDx, Counsyl and 4 other submitters; and as benign by Color, Invitae and Integrated Genetics) and LOVD 3.0 (observed 14x). The variant was identified in control databases in 459 of 268,284 chromosomes (2 homozygous) at a frequency of 0.002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 404 of 118,138 chromosomes (freq: 0.003, increasing the likelihood that this is a low frequency benign variant), Other in 13 of 6704 chromosomes (freq: 0.002), Finnish in 19 of 25,102 chromosomes (freq: 0.0008), African in 14 of 23,600 chromosomes (freq: 0.0006), Ashkenazi Jewish in 3 of 9860 chromosomes (freq: 0.0003), South Asian in 4 of 30,522 chromosomes (freq: 0.0001), and Latino in 2 of 35,106 chromosomes (freq: 0.00006); it was not observed in the East Asian population. The Gly264Ser variant showed some evidence of association with malignancies in the subgroup of hereditary breast and ovarian cancer families (odds ratio=3.44, confidence interval=1.51'Ai7.80, p=5.32*10'Ai3; Meindl 2009). In addition, expression of the variant only partially restored the MMC sensitivity of RAD51C DT40 cells compared to the wild-type cDNA, suggesting the possibility of a hypomorphic mutation with reduced protein activity (Meindl 2009, Somyajit 2012). However, this variant has been identified in multiple cases with co-occurring, pathogenic variants (BRCA1 p.Tyr1463*, BRCA2 c.8632+1G>T, and BRCA2 p.Lys944*; Integrated Genetics internal data per ClinVar submission dated 25 Jan 2018); this decreases the likelihood that this RAD51C variant has clinical significance. The p.Gly264 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T;T;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.010	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.3	.;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.6	.;D;.
REVEL	Benign	0.20
Sift	Uncertain	0.014	.;D;.
Sift4G	Benign	0.45	T;T;D
Polyphen		0.057	.;B;.
Vest4		0.64
MVP		0.69
MPC		0.25
ClinPred		0.028	T
GERP RS		6.0
Varity_R		0.58
gMVP		0.52

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: rs147241704; hg19: chr17-56787304; COSMIC: COSV104641800; COSMIC: COSV104641800;