17-58709937-T-G

Position:

chr17-58709937-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_058216.3(RAD51C):c.784T>G(p.Leu262Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000113 in 1,612,926 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00012 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

RAD51C
NM_058216.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:20B:1

Conservation

PhyloP100: 1.42

Variant links:

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]

RAD51C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD51C	NM_058216.3 link	c.784T>G	p.Leu262Val	missense_variant	5/9	ENST00000337432.9	NP_478123.1	O43502-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD51C	ENST00000337432.9 link	c.784T>G	p.Leu262Val	missense_variant	5/9	1	NM_058216.3	ENSP00000336701.4		O43502-1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152174

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:

0.000191

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251432

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.0000462

Gnomad NFE exome

AF:

0.0000967

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000112

AC:

163

AN:

1460752

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

726808

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.000139

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000125

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74340

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:

0.000191

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000134

Hom.:

Bravo

AF:

0.000102

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:20Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 3

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 10, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jun 04, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 31, 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]. -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2024	Observed in individuals with breast, ovarian, colon, or pancreatic cancer, but also in controls (PMID: 21990120, 24504028, 26261251, 26740214, 28767289, 28135145, 29522266, 30426508, 32659497, 33471991, 35039523); Published functional studies demonstrate normal homology-directed repair (HDR) activity in vitro (PMID: 37253112); In silico analysis supports a deleterious effect on splicing; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25470109, 23117857, 27527004, 29522266, 21990120, 26261251, 25086635, 28135145, 24504028, 26740214, 28767289, 32659497, 33471991, 31874108, 30426508, 26580448, 35980532, 35039523, 30306255, 32885271, 29416752, 14704354, 37253112) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 22, 2023	The RAD51C c.784T>G (p.Leu262Val) variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMIDs: 26740214 (2016), 26261251 (2015), 24504028 (2014), 21990120 (2012)), pancreatic cancer (PMID: 32659497 (2020), 28767289 (2017), 28135145 (2017)), as well as in healthy controls (PMID: 26261251 (2015)). Additionally, the variant has been reported in a large-scale breast cancer association study, and was observed in individuals with breast cancer as well as in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/RAD51C)). The frequency of this variant in the general population, 0.00022 (11/50798 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on RAD51C mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 07, 2023	This missense variant replaces leucine with valine at codon 262 of the RAD51C protein. Computational prediction suggests that this variant may not impact protein structure and function. A functional study has reported the mutant protein to exhibit normal interaction with its binding partners (PMID: 36099300). This variant has been reported in individuals affected with breast, ovarian, and pancreatic cancer (PMID: 21990120, 24504028, 26261251, 26740214, 28767289, 32659497, 35039523, 36099300), and with a pathogenic ATM co-variant in an individual affected with colon cancer (PMID: 28135145). This variant has also been reported in an unaffected individual in a case-control study of ovarian cancer (PMID: 26261251). In a large breast cancer case-control meta-analysis, this variant has been observed in 25/60441 cases and 13/53448 controls (OR=1.701, 95%CI 0.87 to 3.324, p-value=0.143; PMID: 33471991). This variant has been identified in 20/282828 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in 5 individuals age 70 years or older without cancer by FLOSSIES. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 02, 2024	The c.784T>G variant (also known as p.L262V), located in coding exon 5 of the RAD51C gene, results from a T to G substitution at nucleotide position 784. The leucine at codon 262 is replaced by valine, an amino acid with highly similar properties. This alteration has been identified in individuals diagnosed with breast and/or ovarian cancer (Thompson ER et al. Hum. Mutat. 2012 Jan;33:95-9; Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7; Jønson L et al. Breast Cancer Res. Treat. 2016 Jan;155:215-22; Hauke J et al. Cancer Med. 2018 04;7:1349-1358; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This alteration has also been reported in an individual diagnosed with pancreatic cancer (Shindo K et al. J. Clin. Oncol. 2017 Oct;35:3382-3390). Additionally, in a homology-directed DNA repair (HDR) assay, this alteration showed a functionally normal read-out (Hu C et al. Cancer Res, 2023 Aug;83:2557-2571). This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in an incomplete splice defect in the set of samples tested; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). Based on the available evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Sep 10, 2021	- -

Fanconi anemia complementation group O

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 10, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 262 of the RAD51C protein (p.Leu262Val). This variant is present in population databases (rs149331537, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer, ovarian cancer, pancreatic cancer, colon cancer (PMID: 21990120, 26261251, 26740214, 28135145, 28767289). ClinVar contains an entry for this variant (Variation ID: 128210). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RAD51C protein function with a negative predictive value of 80%. Studies have shown that this missense change is associated with inconclusive levels of altered splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 30, 2024	Variant summary: RAD51C c.784T>G (p.Leu262Val) results in a conservative amino acid change located in the DNA recombination and repair protein Rad51-like, C-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.7e-05 in 261730 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RAD51C causing Hereditary Breast And Ovarian Cancer Syndrome (5.7e-05 vs 6.3e-05), allowing no conclusion about variant significance. c.784T>G has been reported in several patients with breast and/or ovarian cancer, colorectal cancer and pancreatic cancer (Thompson_2011, Cunningham_2014, Song_2015, Jonson_2016, Yurgelun_2017, Shindo_2017, etc), without clear evidence supporting pathogenicity. In a study (Song_2015), the variant was found to be slightly overrepresented in ovarian cases (4/3429) than in controls (1/2772). One internal case tested for inherited cancer panel also carried a pathogenic variant in ATM c.1339C>T (p.Arg447X). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25086635, 30306255, 24504028, 33471991, 32659497, 26740214, 23117857, 32885271, 31874108, 29416752, 30426508, 28767289, 26261251, 25470109, 21990120, 28135145). ClinVar contains an entry for this variant (Variation ID: 128210). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

RAD51C-related disorder

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 28, 2024	The RAD51C c.784T>G variant is predicted to result in the amino acid substitution p.Leu262Val. This variant has been reported as a variant of uncertain significance in multiple individuals with BRCA1/2-negative breast/ovarian cancer (for example, see Thompson et al. 2012. PubMed ID: 21990120; Cunningham et al. 2014. PubMed ID: 24504028; Lerner-Ellis et al. 2021. PubMed ID: 32885271) and one individual with pancreatic cancer (Shindo et al. 2017. PubMed ID: 28767289). However, it has also been reported in an individual with colorectal cancer who was heterozygous for pathogenic variants in the ATM and KRAS genes (Yurgelun et al. 2017. PubMed ID: 28135145). In vitro studies suggest that this variant does not significantly alter protein-protein interactions between RAD51C and its binding partners relative to wild type (Prakash et al. 2022. PubMed ID: 36099300). Additionally, this variant is predicted to generate a cryptic splice donor site by available in silico splicing prediction programs (Alamut Visual Plus v1.6.1; https://spliceailookup.broadinstitute.org/), but this has not been directly confirmed by functional studies or RNA sequencing analysis. This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is classified as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/128210/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 07, 2017	The RAD51C c.784T>G (p.Leu262Val) variant has been reported in three studies and is found in a heterozygous state in five individuals with cancer, all of whom were negative for variants in BRCA1/2 (Thompson et al. 2012; Song et al. 2015; Jonson et al. 2016). Four of the individuals had epithelial ovarian cancer and one male individual had prostate cancer. The p.Leu262Val variant was found in one of 6398 control chromosomes and is reported at a frequency of 0.000126 in the European (non-Finnish) population of the Genome Aggregation Database. Although this variant has not been reported in any individuals with Fanconi anemia, it is known that RAD51C heterozygous variants can also confer carrier status for Fanconi anemia. Based on the evidence, the p.Leu262Val variant is classified as a variant of unknown significance but suspicious for pathogenicity for RAD51C-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 14, 2021

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The RAD51C p.Leu262Val variant was identified in 6 of 12090 proband chromosomes (frequency: 0.001) from individuals or families with breast and ovarian cancer and was present in 1 of 4854 control chromosomes (frequency: 0.0002) from healthy individuals (Jonson 2015, Song 2015, Thompson 2012). The variant was also identified in the following databases: dbSNP (ID: rs149331537) as With Uncertain significance allele, ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae, Counsyl, Color Genomics), and LOVD 3.0 (2X). The variant was not identified in the Cosmic or MutDB databases. The variant was identified in control databases in 19 of 277192 chromosomes at a frequency of 0.000069 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 24034 chromosomes (freq: 0.00004), Other in 1 of 6466 chromosomes (freq: 0.0002), European Non-Finnish in 16 of 126684 chromosomes (freq: 0.0001), European Finnish in 1 of 25790 chromosomes (freq: 0.00004), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, and South Asian populations. The p.Leu262 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Leu262Val variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In addition, Human Splicing Finder (HSF) splice analysis showed the possible introduction of a cryptic donor site caused by c.784T>G (Thompson 2012). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Ovarian neoplasm

Uncertain:1

Uncertain significance, no assertion criteria provided

curation

Leiden Open Variation Database

Aug 25, 2011

Curator: Arleen D. Auerbach. Submitter to LOVD: Ian Campbell. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.055

T;T;.

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Benign

0.037

MetaRNN

Benign

0.29

T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Uncertain

2.8

.;M;.

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-2.4

.;N;.

REVEL

Uncertain

0.31

Sift

Benign

0.042

.;D;.

Sift4G

Uncertain

0.038

D;D;D

Polyphen

0.88

.;P;.

Vest4

0.65

MVP

0.76

MPC

0.62

ClinPred

0.42

GERP RS

1.9

Varity_R

0.37

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.71

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.71

Position offset: -5

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