rs61758784

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000337432.9(RAD51C):c.376G>A(p.Ala126Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00494 in 1,612,814 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A126V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0034 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0051 ( 30 hom. )

Consequence

RAD51C
ENST00000337432.9 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:29

Conservation

PhyloP100: 5.81

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 Benign. Variant got -18 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in ENST00000337432.9

BP4

Computational evidence support a benign effect (MetaRNN=0.012307972).

BP6

Variant 17-58695161-G-A is Benign according to our data. Variant chr17-58695161-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 132721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-58695161-G-A is described in Lovd as [Likely_benign]. Variant chr17-58695161-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00338 (514/152210) while in subpopulation NFE AF= 0.00559 (380/68008). AF 95% confidence interval is 0.00512. There are 3 homozygotes in gnomad4. There are 238 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD51C	NM_058216.3 linkuse as main transcript	c.376G>A	p.Ala126Thr	missense_variant	2/9	ENST00000337432.9	NP_478123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD51C	ENST00000337432.9 linkuse as main transcript	c.376G>A	p.Ala126Thr	missense_variant	2/9	1	NM_058216.3	ENSP00000336701	P2	O43502-1

Frequencies

GnomAD3 genomes

AF:

0.00338

AC:

514

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00393

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00559

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00352

AC:

879

AN:

250008

Hom.:

AF XY:

0.00367

AC XY:

496

AN XY:

135154

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00328

Gnomad ASJ exome

AF:

0.00429

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00171

Gnomad FIN exome

AF:

0.000324

Gnomad NFE exome

AF:

0.00541

Gnomad OTH exome

AF:

0.00574

GnomAD4 exome

AF:

0.00511

AC:

7459

AN:

1460604

Hom.:

Cov.:

AF XY:

0.00510

AC XY:

3706

AN XY:

726376

show subpopulations

Gnomad4 AFR exome

AF:

0.000957

Gnomad4 AMR exome

AF:

0.00325

Gnomad4 ASJ exome

AF:

0.00418

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00149

Gnomad4 FIN exome

AF:

0.000525

Gnomad4 NFE exome

AF:

0.00602

Gnomad4 OTH exome

AF:

0.00474

GnomAD4 genome

AF:

0.00338

AC:

514

AN:

152210

Hom.:

Cov.:

AF XY:

0.00320

AC XY:

238

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.00113

Gnomad4 AMR

AF:

0.00393

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000831

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00559

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00593

Hom.:

Bravo

AF:

0.00343

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00640

AC:

ExAC

AF:

0.00348

AC:

422

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00654

EpiControl

AF:

0.00610

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:29

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:8

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	RAD51C: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:7

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 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	Genetic Services Laboratory, University of Chicago	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 14, 2020	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 06, 2018	- -

Breast-ovarian cancer, familial, susceptibility to, 3

Benign:5

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Oct 19, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 10, 2023	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Jun 10, 2016	- -

Hereditary cancer-predisposing syndrome

Benign:4

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 16, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 28, 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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	May 20, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Dec 01, 2017	- -

Fanconi anemia complementation group O

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Jun 10, 2016	- -

Breast and/or ovarian cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

May 15, 2019

- -

Malignant tumor of breast

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The RAD51C p.Ala126Thr variant was identified in 70 of 11449 proband chromosomes (frequency: 0.006) from individuals or families with hereditary breast and ovarian cancer (Akbari_2010_20723205, Blanco_2014_25086635, Clague_2011_21980511, Coulet_2013_22725699, Jonson_2015_26740214, Kushnir_2012_23117857, Leeneer_2012_22370629, Lu_2012_22476429, Meindl_2009_20400964, Romero_2011_ 21537932, Scheckenbach_2014_24315737, Thompson_2012_21990120, Vuorela_2011_21750962, Wong_2011_21409391). The variant was also identified in dbSNP (ID: rs61758784) as â€šÃ„ÃºWith other alleleâ€šÃ„Ã¹, ClinVar (as likely benign by PreventionGenetics and Counsyl, as benign by Invitae, GeneDx, Ambry Genetics, Color Genomics, and Quest Diagnostics), Clinvitae (as benign and likely benign), LOVD 3.0 (9x), and Zhejiang Colon Cancer Database (2x). The variant was not identified in Cosmic or MutDB databases. The variant was identified in control databases in 955 of 275828 chromosomes (3 homozygous) at a frequency of 0.003462 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 28 of 23954 chromosomes (freq: 0.001169), Other in 31 (1 homozygous) of 6444 chromosomes (freq: 0.004811), Latino in 109 (1 homozygous) of 34292 chromosomes (freq: 0.003179), European (Non-Finnish) in 684 (1 homozygous) of 125890 chromosomes (freq: 0.005433), Ashkenazi Jewish in 43 of 10090 chromosomes (freq: 0.004262), European (Finnish) in 8 of 25752 chromosomes (freq: 0.000311), and South Asian in 52 of 30556 chromosomes (freq: 0.001702), while the variant was not observed in the East Asian populations. The variant is classified as a benign polymorphism in the literature (Akbari_2010_20723205, Clague_2011_21980511, Coulet_2013_22725699, Jonson_2015_26740214, Kushnir_2012_23117857, Leeneer_2012_22370629, Lu_2012_22476429, Meindl_2009_20400964, Osorio_2012_22451500). In vivo yeast functional studies have shown no detectable difference in expression versus the wild type allele (Clague_2011_21980511). In addition, Jonson (2015_26740214) has reported that the variant to be co-occurring in three individuals with a disease-causing RAD51C (c.945dupT), BRCA1 (p.Gln563Ter) or BRCA2 (c.5164_5165delAG) mutation, increasing the likelihood that the p.Ala126Thr variant does not have clinical significance. The p.Ala126Thr residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.016

T;T;T;.;T;T

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.94

D;D;D;D;D;D

M_CAP

Benign

0.0093

MetaRNN

Benign

0.012

T;T;T;T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Uncertain

2.3

.;.;M;M;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.8

.;.;N;N;N;.

REVEL

Benign

0.10

Sift

Benign

0.14

.;.;T;D;T;.

Sift4G

Benign

0.27

T;T;T;T;T;T

Polyphen

0.066

.;.;B;.;.;.

Vest4

0.48, 0.48, 0.19

MVP

0.75

MPC

0.31

ClinPred

0.021

GERP RS

3.4

Varity_R

0.17

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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